Reedus' first film was in the 1997 Guillermo del Toro horror thriller film Mimic, where he played the character Jeremy. He also had roles in the films Dark Harbor, Six Ways to Sunday, Deuces Wild, Blade II, Gossip, 8mm, American Gangster, Hero Wanted, and Moscow Chill. In 2005, he had a bit part in the Christian Alvart film Antibodies as a German policeman. In 2008, he starred in the film Red Canyon. Reedus played Murphy MacManus in the 1999 movie The Boondock Saints. He reprised the role in the 2009 sequel The Boondock Saints II: All Saints Day. He guest-starred on Charmed as Paige's (Rose McGowan) boyfriend, Nate. Reedus also starred in the film Hello Herman, which opened nationwide and on-demand on June 7, 2013. Reedus is starring in a six-episode reality mini-series Ride with Norman Reedus, which premiered on June 12, 2016.
In 2010, Reedus began playing Daryl Dixon in the AMC television series The Walking Dead, a horror drama about a group of friends and family members who fight to survive in a violent apocalyptic world populated with flesh-eating zombies and the few surviving humans, some of whom are even more diabolical and dangerous than the zombies themselves. The character was not originally in the comic book series of the same name, but was created specifically for Reedus after his audition for the character of Merle Dixon. The Walking Dead comic creator Robert Kirkman feels, "absolutely blessed Reedus has honored the show with his presence, and the way he has come in and taken over that role and defined Daryl Dixon. A lot of Reedus's portrayal of the character in the first season inspired all the writers to do what we did with him in the second season. We love writing him and end up doing cool stuff with him." The drama has evolved into the highest-rated in cable history, smashing all previous records. Reedus was nominated for a 2012 Saturn Award for Best Supporting Actor for his portrayal of Dixon.