All spoilers are unmarked per wiki policy. Read only at your own risk. You Have Been Warned.
- The "Funeral Party" mission scene where the Vagos mourn their fallen. Even sadder, is that ultimately the funeral was exploited to smuggle drugs.
- The fact that Ron is pretty much all alone and without anyone after Trevor became a life coach in "Smuggler's Run". Keep in mind, Ron used to be a functioning person who had a wife until he met Trevor which caused him to become the nutcase he is today...now that Trevor's out of the picture, and assuming he and Wade don't hang out, Ron is by himself with absolutely nothing, almost as if associating with Trevor was All for Nothing. The fact that the protagonist is the only active friend he has now can be depressing.
- He hits rock bottom in the Los Santos Drug War Updates, where everything he and Trevor once owned and achieved was taken over by the Fooliganz thanks to Wade informing them about Trevor's abandoned properties. Ron getting pummeled by Luchadora can arguably be seen as an equivalent to Klebitz' fall from grace, and with the fact that the player essentially abandons him to help the Fooliganz much to his chagrin, all he's got left is Chef at this point, who may or may not have died from overdosing thanks to Labrat. Ron nor Chef are seen for the rest of the update after the first mission. By the time San Andreas Mercenaries rolls around, he's outright begging for the player to come back to work with him again.
- Surprisingly enough, the Diamond Casino & Resort plotline has a couple:
- If one of the players end up driving Agatha instead of Tao's translator, she starts lamenting that she's gotten herself caught up in criminal business and going off about what she wanted to do with her life in actuality. Though it's meant to be Played for Laughs, it's kind of hard not to feel bad for her given that she only wants to sell and run a casino, not get involved in life-threatening situations.
- Tao's translator was clearly shook by Wei Cheng's implied death at the hands of Franklin, even though he deserved it. So much so that he gets panicky every single time that Tao starts to get too brave.
- The arc basically ends with The Duggans getting what they wanted and the Chengs losing their Casino; Granted, the Casino ends up in the hands of Thornton instead of the late Avery, but the fact still remains Tao failed. After all the attempts to fight off the Duggans at Tao's request, ultimately he's forced against his will by Mr. Cheng to surrender after a direct assault and sell off the Casino at the risk destroying it in attempting to keep it much to his chagrin, Agatha is essentially scarred for life after dealing with what she's dealt with, and Vincent is fired by Thornton at the very end despite his hard work throughout the entire arc (and he shows visible sadness at being fired). If not for the fact that the Casino that took 5 years to finish was essentially saved from pointless destruction at the hands of Tao and Avery, with everyone but Vincent being able to keep their jobs thanks to Thornton, and Thornton eventually getting robbed by a crew organized by the Chengs in retaliation later on...this would have been nothing short of a Downer Ending.
- The fact that the best that Jimmy De Santa could aspire to is being a janitor. While played for laughs in-game, if you think about the fact that Tracey is in college, it becomes sadder given the direct contrast with Jimmy having little to no progress with his life as of The Diamond Casino Heist given it takes places a long time after the single player story.
- The look of disappointment Lester shows when he finds out that Georgina Cheng went back to China in the Casino Heist Mission's pre-heist intro.
- In the Cayo Perico Heist aftermath, as Miguel Madrazo calls up his father to excitedly tell him about what he and the crew he hired managed to do in Cayo Perico, and starts bringing up investment ideas, his father coldly hangs up without a single thank you or response, leaving him feeling rejected as a son...although brief, you can feel the dejection Miguel has in his voice and on his face. Then when he sees that the blackmail material El Rubio had on his father wasn't as groundbreaking as he thought, he just walks off looking completely spirit-broken after throwing it all in the pit fire, leaving his own mother to thank the player for helping the Madrazos out.
- It gets more depressing when you think about the fact that Martin isn't only nasty and neglectful of his own wife...even his own son, who's doing everything he can to impress his father and show he's fit to lead the Madrazo Cartel when the time comes.
- Although El Rubio is undoubtedly an Asshole Victim who keeps getting robbed every day constantly by the Online Protagonist, from hearing some of his announcements on the PA system you can't help but feel a tiny bit of sympathy for the guy, as he is pretty much trapped on an island he can't leave from because of Globalpol, and has to endure being robbed on a regular basis. Almost like this is a worse prison for him.El Rubio: This is what happens when you're too trusting huh? I just wanted people to have fun. This sucks so much! it's so unfair!El Rubio: I won't run, They won't win. This is meant to be my island paradise, it’s turned into my personal hell, but I’m not leaving!
- While mainly Played for Laughs, just seeing Lamar's desperation to get his business off the ground and failing to during The Contract arc is kind of sad to see. Thankfully, this changes in the "Short Trips" storyline that occurs directly after Dr. Dre gets his phone back.