Three serious mistakes
First of all, in general I'm barely aware of the differences between the comic and the show. I never got into the former, so I'm not invested in it at all.
I think that in the show they did three major characters mistakes:
Andrea: she had potential as a badass fighter essential to the survival of the group, but the writers chose to ruin her character and to kill her just for the sake of it. Her caharacter wasn't beyond repair and could've been a better partner for Rick (see below).
Pairing Rick and Michonne: on paper it made sense, but AL and DG couldn't sell the relationship. They were better off as friends because they had less than zero romantic chemistry. Hell, Rick had better chemistry with Jesse. It was like looking at siblings making out. Ick!
Carl: killing off Carl was a huge mistake. I get it, CR was almost a grown up and couldn't act to save his life, but come on. The story has always been about Rick doing everything he could to ensure his son's survival.
Honorable mentions:
Merle: MR was really good and Merle had still some untapped potential to become a regular. For a while longer at least.
Gabriel: he definitely overstayed his welcome. He should've been killed during the war with Negan.