He is known for his roles as Crashdown in Battlestar Galactica, Davis Bloome in Smallville, Aidan Waite in Being Human, Mr. Hyde in Once Upon a Time, Ben Lockwood in Supergirl, and Rupert Chipping in Riverdale.

Witwer portrayed protagonist Deacon St. John through motion capture for the video game Days Gone by Bend Studio.

[8] From 2008 to 2009, Witwer was cast in season 8 of Smallville as Davis Bloome, a charming paramedic who struggles with a darkness within as he is the human camouflage of Doomsday.

Witwer's performance in Smallville was incredibly well-received, and he has stated that his experience on the show had opened more opportunities for him in the future of acting.

Though he considered his time on the show enjoyable and was flattered by the offer to stay on, he passed on the role as he felt it would be difficult for both the characters and audience to accept.

[10] Coincidentally, in 2019 he went on to portray the main protagonist (both voice and motion capture) of a video game called Days Gone, which also tackles the topic of zombie apocalypse.

[19] In January 2017, he appeared as a guest on a play-through of ScratchPad Publishing's Dusk City Outlaws, alongside Elisa Teague, Tom Lommel, Spencer Crittenden, and game designer Rodney Thompson.

He also voiced Darth Sidious (Emperor Palpatine) in the first game, and reprised it for the games Disney Infinity 3.0 and Battlefront and for the original season 2 premiere of Star Wars Rebels;[21] however, in 2019, the role was re-dubbed by Ian McDiarmid who portrayed Palpatine in the films and in Rebels season 4.

[23] On September 27, 2012, a feature-length "director's cut" of Witwer's season 4 finale episodes of The Clone Wars were released as a direct-to-video film, Darth Maul Returns, initially made available exclusively at Target.

[24] Witwer attended The Clone Wars season 5 Red Carpet Premiere in Orlando, Florida on August 24, 2012, during Celebration VI along with some of his co-stars Matt Lanter, James Arnold Taylor, Dee Bradley Baker, Tom Kane, Daniel Logan, Stephen Stanton and Ashley Eckstein, as well as Supervising Director Dave Filoni.

Witwer has also voiced an alien as well as a First Order stormtrooper during the siege of Maz Kanata's palace in Star Wars: The Force Awakens.

[28] In 2020, Witwer was cast as an unidentified dark side character in the StarWarsKids.com and YouTube game show Star Wars: Jedi Temple Challenge, which premiered on June 3, 2020.