A number of alterations have been made from the original Resident Evil 2. However, unlike the remake of the original Resident Evil, which more or less supplanted the first game's story by introducing new plot threads, here the narrative changes are more self-contained, and don't add onto or contradict with anything that takes place afterward in Resident Evil canon in any significant ways.
- A deliberate point is made of changing some of the more iconic scares for the sake of keeping the player on their toes. For example, the Licker's debut scene is replaced with simply finding another dead body impaled, while your first quick glimpse of the monster skittering across a window now occurs on the third floor. This is averted in the 2nd Run, where the first glimpse of the Licker appears at the first floor window and corridor like the original game.
- Several weapons have been moved around. Whereas Claire and Ada both started their sections with a Browning Hi-Power in the original, they are given new starting weapons in the remake, with the pistol being relegated to being optional loot during the former's playthrough only. The MAC-11/MQ 11 is now available only to Claire as well, and is found in the S.T.A.R.S. weapon closet instead of the precinct armory, and is no longer given for free upon starting a new game on the easiest difficulty.
- In the original game, Marvin states that he knew the Mansion Incident from the first game was related to what occurred in Raccoon City. In this game, when he's asked about the situation, he states that he doesn't have any idea. The letter you find from Chris suggests he and the other S.T.A.R.S. members gave up on trying to convince their associates after Chief Irons stonewalled them, so Marvin never had any warning.
- Speaking of the letter, it's made to be more a subtle code. He's comically pretending to not take the mansion murders seriously and instead enjoy a vacation. But the mention of "a really big Umbrella" should tip his fellow S.T.A.R.S. members, his sister, and fans of the first game off about his true intentions. He says Barry shouldn't come with him because it would upset his family if he does, I.E. he needs to stay and keep his family safe from the evil company.
- The remake changes it so that the protagonists' first encounter with Marvin has him saving their lives from a zombie, and then taking refuge in the main hall. In the original game, Marvin is found heavily wounded in the adjacent office instead.
- The journey the 1st Run protagonist takes to the Raccoon Police Department is much shorter, and less of the city is explored. When they begin at the police cruiser wreck, they only need to go down the street and through a single alleyway to immediately arrive at the station's front doors. In fact, looking back from the RPD's front doors shows the duo were a mere block from the station. During a 2nd Run, that protagonist's trip was apparently long enough for the both of them to meet up at the east wing side of the front courtyard about the same time, but said trip occurs purely off screen.
- Only Leon ever gets to visit Kendo's gun shop during either his A or B scenario. He also drops by the store after leaving the RPD precinct instead of en route to the station. Claire skips the place entirely, and the Bowgun she gets there in the original game is completely absent.
- Mr. X's arrival into the RPD isn't shown, whilst in the original game, he was airdropped via an Umbrella helicopter.
- Ada's "looking for my boyfriend" cover story is replaced with her pretending to be an FBI agent who's going after Annette Birkin to get dirt on Umbrella. This also leads to her Adaptational Personality Change as well; whereas the original Ada played up her seductiveness and use of emotional manipulation to meet her goals, remake Ada leans heavily into a colder and more professional attitude with little tolerance for anything that gets in her way.
- Sherry was unaware of her father being the monster that would hunt her throughout the Claire A scenario in the original, at least until the end of the game. In the remake, she recognizes him immediately. In retrospect, this meshes better with the story she tells Jake Muller in Resident Evil 6.
- Claire doesn't have a run-in with G-Birkin's first form, but his second in the Umbrella elevator. In this game proper, she encounters Birkin's first G form after she finds Sherry. Like Sherry's above example, this actually meshes well with her flashback in Resident Evil: Degeneration after being told of the G-Virus.
- Claire's first meeting with Chief Irons no longer occurs in his office, and instead happens in the parking garage, where he displays his true colors immediately by forcing Sherry to tie Claire up at gunpoint and pistol-whipping her before he kidnaps Sherry.
- Claire and Leon don't meet in a diner in Raccoon City. Instead, they encounter each other at a gas station on the outskirts of the city, and head into the city proper together. In addition, there's no zombie in the backseat of their cruiser. They instead are split up when their cop car comes upon a barricade, electing to go on foot to the RPD, when suddenly their cruiser is attacked by zombies on both sides, and a tanker truck bears down on them and crashes.
- The RPD no longer has any secret passageways to the sewers and the Umbrella lab, save for a small hidden elevator in one of the sewer offices. The main characters have to leave the police station to find their way underground.
- The RPD's standard cruiser is now primarily 1977-1990 Chevrolet Caprices, with the 1991-1997 Crown Victoria Police Interceptor nowhere to be seen (Leon and Claire notably used one in the 1998 version).
- Raccoon City is greatly enlarged in size, and is now an actual city, with high rise buildings, a subway system, far denser urban sprawl, giving it a metropolitan vibe more befitting its status as the "home of Umbrella" and population of 100,000.
- In the original game, the truck driver who gets bitten by a zombie is shown to have become a zombie while still behind the wheel before crashing into Leon and Claire. The remake changes this scene a bit by showing the driver is still human, but clutching where he got bit by the zombie. The driver then passes out from his wounds and he crashes the truck. Likewise, the driver's first scene in the original game shows him throwing a zombie through the window of a gas station and fleeing into his truck after he gets bit by it. The remake shows the driver accidentally running a zombie over, whom he assumed to be a normal human, and stops to try and help them, while getting bit for his troubles offscreen.
- In the original game, Ben didn't know anything about what was going on except that Chief Irons was in bed with Umbrella. Here, Leon finds a tape recorder on his dead body containing an interview with Annette, whom he attempts to grill for info on the G-Virus and Umbrella's underground lab. He also finds a note saying that Ben knows about the Tyrant and how it's probably been ordered to kill anyone who knows about Umbrella's involvement in the outbreak. Like him.
- The Plastic Explosives item is used to demolish a broken doorway from the chopper crash in the original in order to gain access to Chief Irons' office, while the remake instead has the protagonists using it to unblock the way leading to the Medallion on the precinct's third floor.
- Leon gets shot by Annette before fighting the giant Sewer Gator in the original, whereas the remake reverses this order of events. This makes more sense as the gunshot wound would likely get infected as Leon fights the gator inside a spillway this time around. Making it so that he gets shot after tumbling around in dirty water solves this issue.
- This is one of the only games in the franchise set before RE4 in which there are two magnums, and the way you obtain one of them (the one specific for Claire) is by upgrading one of your previous starting guns, to chamber higher caliber rounds.
- Sherry's locket in the original game contained a sample of the G-Virus, which Mr. X was programmed to retrieve. Here, it's just an ordinary locket, but acts as a key Claire uses to unlock the case containing the Devil Vaccine.
- In the original game, Mr. X would only stalk the player while playing through the B scenario, where his directive is to retrieve the G sample hidden in Sherry's pendant. The remake integrates him into both A and B, while also giving him a new reason to be there: to silence anyone who is or could be a potential witness to Umbrella's part in the Raccoon City outbreak. Also, only Leon gets to fight his One-Winged Angel form this time around in a completely different area, while Claire gets to battle a new mutation of G-Birkin in the turntable shaft.
- Speaking of Mr. X and the locket... in the original, Mr. X tried to get the G-Virus sample from it in either B scenario and ended up damaging the controls in the Power Room, initiating the self-destruct sequence. In Leon's scenario of the remake (both A and B), Leon takes the G-Virus sample from the lab without any authorization, inadvertently initiating the self-destruct sequence in a matter of minutes.
- The reason Mr. X loses his Power Limiter coat has been changed. Basically, the entire scene where he stumbles into a vat of molten steel after being shot by Ada was removed (due to making Ada's "death" from Leon A the canon), and he instead loses his coat in a gas explosion that also disfigures him. As such, his One-Winged Angel form is also markedly altered, and no longer is he fought in the turntable control area, the entire battle being relegated to a funicular ride down to the train tracks instead.
- The cable car encounter was merged with Birkin 2.
- How the G-Virus sample was lost in Leon's campaign changes in the remake. The original version's Leon A scenario had Leon throw the virus down the central shaft in anger after witnessing how far Annette and Ada were willing to go to get it — in Leon B, the G-Virus sample remains in Ada's possession after her presumed death at Mr. X's hands. In the remake, the virus is dropped down the shaft after Annette shoots Ada while proclaiming that no one will get it now.
- The Club and Heart Keys were slightly changed in the remake. While Leon and Claire were able to get both keys in the original game, the remake has it where only Leon can get the Club Key, while Claire is the only one who gets the Heart Key. This means that Leon never gets to explore Chief Irons' office and the storage room on the third floor, while Claire doesn't have access to the storage room containing the Club Key due to the door being boarded up in her scenario.
- The ending was given a slight change. In the original, Leon says it's time for them to go and take out Umbrella (Leon B), while Claire's ending has her wanting to continue her mission to find Chris (Claire B). The remake has the ending the same for both characters and it has them wandering down a highway, waving at a passing truck and them being flipped off by the driver. Leon and Claire then decide they'll do whatever it takes to prevent another viral outbreak, while Sherry proposes that the two should adopt her and get a puppy.
- Annette has been made slightly more sympathetic; rather than callously ignoring Sherry in favor of her research, her motive is now trying to put an end to her husband in his now monstrous form before he causes an epidemic. Accordingly, rather than approaching William's G3 form and getting butchered, she instead tries to help Claire/Leon take him down (using a flare gun converted into a miniature grenade launcher) and is attacked when he turns out to be Not Quite Dead.
- Instead of the various weapons being mutually exclusive to each scenario, they're fixed for each character. Both get one improved weapon from the weapons locker (which can have more ammo crafted by combining normal and high grade gunpowder)note , another improved weapon from the S.T.A.R.S. room (which can have ammo crafted by combining two high grade gunpowers)note and a final weapon for solving the plug room puzzle in the sewers (for which ammo is extremely rare and cannot be crafted)note . All three weapons can be upgraded (with one upgrade for the first two that causes it to take up two inventory slots) with the upgrades for each respective weapon showing up in the same places. In addition, Claire can find a slightly better pistol early on in the car park (where Leon finds an upgrade for his pistol instead), and can upgrade her starting pistol to fire magnum rounds in the sewers.
- The locations of many of the weapons have been changed so that they can be found in roughly the same areas regardless of if you're playing as Leon or Claire, in either the A or B scenario. The most egregious example of this is how the Spark Shot and Flamethrower have been changed from the original. Whereas both are found in separate areas of NEST in the classic, the Spark Shot on the body of a zombie and the Flamethrower in a locker, the remake puts both of them in a specialized holding area in the sewers that must be unlocked via Solve the Soup Cans. To make matters more confusing, both are found in the same room, on the same plaque, despite the fact that both scenarios are supposed to be running concurrently in a single timeline.
- In the original game, Leon was late for his first day because he broke up with his girlfriend and drank so much that he overslept. In the remake, this has been changed to him getting a phone call to stay away from Raccoon City and wait for further orders. After a week of complete silence, Leon enters the city by himself to investigate.
- Ada's fake death is almost the same as Leon A in both scenarios, even that her eventual fate in the series canon was the Leon B one.
- The ending of the second scenario involving Birkin's final form got a change in the remake. In the 1998 original, you pump Birkin full of lead, find out that he's still alive, and the player character hangs from under the train to avoid him while Sherry hits the emergency brakes to stop the train. The protagonists then ditch the train and run out of the tunnel as the train explodes, which kills Birkin for good. In the remake, rather than run away from Birkin, the player character grabs a pipe and stabs Birkin in the eye to send him reeling. The protagonist then detaches the coupling so the car Birkin is in falls behind and gets consumed by the fireball caused by the lab's self destruct. The train itself doesn't blow up.
- Leon and Claire's meet up at the police station was changed. In the original game, they met up in either the S.T.A.R.S. Office (Leon A/Claire B) or in the lobby next to the Library (Leon B/Claire A). The remake changes their meetup to the staircase outside in the east wing of the station and it applies to both runs. While the original also gave both characters a radio to keep in touch, the remake doesn't do this, thus the two don't get to talk to each other until the escape sequence from the lab.
- Annette's death is significantly changed. The original had her either dying from her injuries after debris falls on her head (Leon A) or dying to Birkin's G form via slashing (Claire A). The remake merges both scenes together where she's heavily wounded from Birkin and either dies after saving Sherry (Claire scenario) or dies after shooting Ada (Leon scenario).
- In the original game, Robert Kendo was some random guy Leon/Claire encountered in a gun shop shortly after the game starts, and is devoured by a gang of zombies not long after his intro. He also never mentioned having any family. In the remake, he had a wife and daughter both of whom he had to Mercy Kill after they became infected, and is completely distraught over the fact he had to do so. There's also an implication that he had a friend who came to get him out of Raccoon City.
- The self destruct sequence was completely revamped. The original gave you five minutes to escape and the escape route you took was based on what scenario you played; scenario A leads you to a room where you fought G one last time while waiting for the elevator to come up and then said elevator took you to the train platform. Scenario B has you take the main elevator directly to the train station, turn on power for the train, and then have a final bout with Mr. X before boarding the train and then fighting G's last form. The remake doubles the escape timer to 10 minutes since you have to go through a few areas before reaching the train. Likewise, no matter which run you play on, Leon will always fight Mr. X near the end and Claire has to deal with G. While the original gave the scenario B character a rocket launcher to finish off Mr. X, the remake makes it a Leon exclusive weapon for his campaign while Claire gets a minigun for hers. The 2nd run character still fights G on the train.
- The joint plugs used in scenario B of the original game were used to give the train area power. In the remake, the plugs not only appear in the train area to power the train, but also appear in Leon's scenario to power an elevator that takes him to the train. The plugs in the remake were also combined into one item but still takes up two slots.
- In the original's B scenario, Mr. X would appear after you powered the elevator leading to the laboratory. Looking at the security console would show Mr. X making his entrance before he destroys the camera. The remake moved this scene to the police station where the 2nd run character looking at the main hall's computer can see Mr. X approaching the camera and destroying it.
- William Birkin's start of his G-Virus mutation has several differences between versions. The original had him barely alive with Annette coming in as he lay dying and running off to get him treatment before he injects a sample into himself. In the remake, Annette walks in after William injected the virus into himself offscreen and he starts to walk away while his whole body twitches. Annette raises a gun on him but can't bring herself to shoot her husband.
- Elliot Edward was given a drastically different design and his death was also changed between games. The original game had him as an overweight cop who almost looked like Chief Irons. Elliot dies by two zombies he tries to shoot with his machine gun and his weapon arcs up as he is tackled, causing it to shoot at the helicopter pilot nearby and making him crash into the group. The remake has Elliot with a slimmer build and he dies from a zombie chewing off his legs as Claire or Leon drag him from under the shutter door.
- The way Leon and Claire learn about how the town came to be infected and how William infected himself after getting shot are changed as well. In the original, Annette told various characters how the spill happened, how William was attacked, and that he injected himself with the G-virus. This made no sense, since she was trying to protect the G-virus. Here, since she is trying to destroy it, she doesn't make small talk with anyone save just before the G3 fight when Claire/Leon pointedly ask her what is going on after finding out for themselves via USS videotapes how the T-virus leaked and how William was cut down and connecting the dots themselves.
- The remake has Sherry being captured and held hostage by Chief Irons while Claire fights her way through the city to rescue her. Sherry and Irons never interacted in the original game and Irons only makes a passing mention of Sherry during his final conversation with Claire.
- In scenario A for the original game, the protagonists had to go through a basketball court and then a bus before reaching the police station. The remake makes these areas exclusive to Claire who has to travel through them to reach the orphanage where Sherry is being held hostage.
- Ada's injury changes between games. The original had her being slashed by G and her injury could be seen on her arm. The remake has her falling into a pit and her leg gets pierced by broken glass. Leon tends to her wound while he didn't do so in the original.
- Sherry's No-Gear Level playable sequence is completely reworked from a weird detour in the sewers into an original sequence set in the Raccoon City Orphanage.
