While the overall story and outline for the movie is the same as the graphic novel, quite a few major changes have been made to either help character motivations or to simply make a slightly happier outcome. A few of the heavy heavy major changes are below:
(1) In the graphic novel, it is not Katie who asks Kick-Ass for help taking care of the low-life drug-dealers at the apartment where Kick-Ass first meets Hit-Girl. It is the ex-girlfriend of the head gang member at the apartment who asks him for the help because her ex-boyfriend keeps harassing her. The said ex-girlfriend of the gang member appears at the end of the graphic novel performing sex acts with Dave's father. This change was probably made in the movie as to a.) keep the plot of the movie more simple by not throwing too many characters and subplots and b.) to get Katie a little bit involved in the conflicts of Kick-Ass.
(2) In the graphic novel, you don't know Red Mist is an insider double-crossing the protagonists until they all meet at a warehouse towards the end, for which, as in the movie, it is revealed that he is the son of John Genovese (the name of the kingpin in the graphic novel, as opposed to Frank D'Amico). In the movie, you know from the get-go that Red Mist is D'Amico's son and is planning to double-cross the protagonists (namely Big Daddy).
(3) Probably the biggest character motivation change is the origin of Big Daddy. While in the movie, Big Daddy really is an ex-cop out for revenge against D'Amico, in the graphic novel, it is revealed in the torture scene that he was only pretending to be an ex-cop turned vigilante, and that in reality, he was an accountant, and that the reason for being a vigilante superhero was, just like Dave, he was a huge superhero comic book fanatic, and that he funded everything for him and Mindy (Hit-Girl, his daughter) by selling a bunch of his old vintage comics he kept locked in a chest from Mindy so Mindy wouldn't know that her father wasn't a cop. He then reveals his motivation for going after the gang and making up the story of his wife's death (who is, in fact, still alive and divorced from him) and his excuse is simply, "We needed a villain." Also, in said torture scene, Big-Daddy's death is a tad bit more gruesome and he dies before Hit-Girl even comes back to the rescue, not being able to say goodbye to him. In the graphic novel, he gets shot in the head with most of his brains coming out, while in the movie he gets burned to death but has time to tell his daughter goodbye. This was probably changed for the movie to give Big Daddy and Hit-Girl real motivation for going after the bad guys and to make the bad guys more, well, bad. Also, because Big Daddy's now ex-wife is revealed to be alive in the graphic novel, it is her (Mindy's/Hit-Girl's mother) that Mindy stays with at the end, not Sgt. Williams like in the movie.
(4) The biggest change overall probably comes at the end with Katie and what happens after Dave reveals himself to not be gay and that he is the real Kick-Ass. In the movie, Dave reveals the truth to Katie before the climax and she then falls in love with him. In the graphic novel, when Dave reveals the truth to Katie, Katie gets really angry and has her new real boyfriend beat Dave up. Afterwards, Katie then repeatedly sends pictures of her performing fellatio on her boyfriend just to make Dave even more miserable. This change garnered the most criticism from fans of the graphic novel, as they believe there was an important moral being told when Katie messed Dave over. However, some of the graphic novel fans do say that the happier outcome works good for the movie because in the long run, it makes the torture scene more emotionally effective, as Katie and many of the city's people are watching Kick-Ass and Big Daddy's torture on the news and Katie is seen crying in fear.
Several minor changes are detailed as follows: Kick-Ass is stabbed after confronting a group of taggers, not carjackers; the setup for the big fight scene where he attempts to recover a cat does not occur; it is Big Daddy and Hit Girl who request Kick-Ass and Red Mist to meet them, not the other way around; there is no such place as Frank's lumber store, and the burning building sequence occurs in a random apartment building where Kick-Ass and Red Mist rescue a trapped cat only to be rescued by firemen themselves; Katie's friend only makes a single appearance and does not even speak; the finale with the bazooka and the jetpack does not occur, instead there is relatively straightforward shootout; John Genovese and Chris (Frank and Chris D'Amico) have very little pagetime at all, as opposed to being major characters in the film; Red Mist is not upset to see Kick-Ass taken and tortured, even going as far as to mention he has had sexual thoughts about his death; Dave's Dad does not simply get over his wife's death, relying on Dave to help him get back into the dating world after a long period of depression.