He became prominent when playing roles in films, like Russell Thompson, Sr. in Honey, I Shrunk the Kids (1989), Jobe Smith in Lawnmower Man 2: Beyond Cyberspace (1996), Sherlock Holmes in the film adaption of The Sign of Four, Frank in Dawn of the Dead (2004), Moloch in Watchmen (2009), Mitch in 50/50 (2011), and Archibald Stanley in Night at the Museum: Secret of the Tomb (2014).

Frewer's more recent performances include a portrayal of "General #2" in the Steven Spielberg picture The BFG (2016), the character Carnage in the Netflix series Altered Carbon in 2018 and Logan in Fear the Walking Dead (2019).

He also portrayed Max Headroom in other media, including a series of television commercials for "New Coke" and "Radio Rentals", as well as the single and music video for "Paranoimia" by Art of Noise.

[8] Frewer has also appeared in such films as The Fourth Protocol (1987), Honey, I Shrunk the Kids (1989),[7][8] National Lampoon's Senior Trip (1995), and the 2004 remake of Dawn of the Dead.

[8] Frewer was nominated for two Gemini Awards in 2000, one for a guest appearance on Da Vinci's Inquest[9] and another for his work on the series Mentors.

[11] He has appeared in several adaptations of Stephen King stories, such as The Stand,[8] Quicksilver Highway, Riding the Bullet, Desperation and Bag of Bones.