- The Other Darrin: Given that the series was produced on a much lower budget, none of the Celebrity Voice Actors from the original movie came back.
- Megamind is voiced by Keith Ferguson, reprising the role from the tie-in video games, instead of Will Ferrell. In a double example, he's also replacing Nolan North, who voiced Megamind in DreamWorks All-Star Kart Racing.
- Roxanne is voiced by Laura Post instead of Tina Fey.
- Minion/Ol' Chum is voiced by Josh Brener instead of David Cross.
- Mayor Jody Smelt is voiced by Roger Craig Smith instead of Stephen Kearin.
- What Could Have Been: The show was originally called Megamind’s Guide To Defending Your City, and it was changed far enough for the characters to say or allude to its old title a few times.
- Working Title: Megamind’s Guide To Defending Your City, which is alluded to several times.
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