Reedus played Jeremy in his major film debut Mimic and Mac in Giovanni Rodriguez’s Red Canyon. Reedus played Murphy MacManus in the 1999 film The Boondock Saints. He reprised the role in the 2009 sequel The Boondock Saints II: All Saints Day. He played Scud in Blade II. He guest-starred in Charmed as Nate, the boyfriend of Paige (Rose McGowan). Reedus starred in Hello Herman, which opened nationwide and on-demand on June 7, 2013. Reedus currently stars in the reality series Ride with Norman Reedus, which premiered in June 2016. Most recently, he started Bigbaldhead Productions with an overall deal at AMC.

In the mid-1990s, while working as a model, he appeared in the music videos for “Wicked As It Seems” by Keith Richards, “Violently Happy” by Björk, “Flat Top” by Goo Goo Dolls, “Cat’s in the Cradle” covered by Ugly Kid Joe, “Strange Currencies” by R.E.M., and “Fake Plastic Trees” by Radiohead. In 1999, he appeared in the video for “Mean to Me” by Tonic. Since achieving fame as an actor, he has also appeared in the videos for “Judas” by Lady Gaga, “Sun Down” by Tricky (ft. Tirzah), “Gypsy Woman” by Hilary Duff, and “No Cities to Love” by Sleater-Kinney.

In February 2005, Reedus sustained a head injury when a truck collided with his car in Germany. His nose was reconstructed with the aid of four screws and his left eye socket with titanium.

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. 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 Saturn Award for Best Supporting Actor for his performance.

He is also a painter, sculptor, and photographer, who currently shows his artwork in galleries in New York City, Berlin, and Frankfurt. He released a book of photography on October 31, 2013, called The Sun’s Coming Up… Like A Big Bald Head, and in September 2014 announced a fan-art compilation called Thanks For All The Niceness.

Reedus reprised his role as Daryl Dixon in the 2013 video game The Walking Dead: Survival Instinct, which is based on the television series. He was set to star in Hideo Kojima and Guillermo del Toro’s reboot horror game Silent Hills, but Kojima left Konami and the game was cancelled in 2015. Reedus starred in Kojima’s new game Death Stranding.

Reedus has modeled for Prada, Alessandro Dell’Acqua, Durban, Levi’s, Lexus, and Morgenthal Fredrics. In 2015, Reedus posed for a Cruelty Free International advertisement in support of ending cosmetic tests on animals.

In 2015, during the filming of Sky, Reedus met Diane Kruger; the two were first seen together as a couple in July 2016. In November 2018, Kruger gave birth to their daughter, her first and his second child.