Combs's best known horror role was as Herbert West, the main character in the movie Re-Animator, which he has reprised in the film's two sequels. He also portrayed the part of author H. P. Lovecraft (creator of the Herbert West character) in 1993's film Necronomicon: Book of the Dead. Combs has starred in eight H.P. Lovecraft adaptations. Other film credits include FeardotCom (2002), House on Haunted Hill (1999), I Still Know What You Did Last Summer (1998) and The Frighteners (1996).
Combs has had roles in many science fiction television series. He starred as the telepath Harriman Gray, in Eyes (1994), a first season episode of Babylon 5. In August 2005, he appeared for the first time on the science fiction series The 4400 as Dr. Kevin Burkhoff; by 2006, this became a recurring role. In early 2007, he played a highly fictionalized Edgar Allan Poe in The Black Cat, an episode of Masters of Horror.
Combs has done extensive voice work, including The Scarecrow in 1997's The New Batman Adventures. Combs continued his work in the DCAU several years later, with a recurring role as The Question in Justice League Unlimited. Combs provides the voice of Ratchet on the new animated series, Transformers: Prime.
He worked besides his acting career, as voice actor for the films The Avengers: Earth's Mightiest Heroes, Teenage Mutant Ninja Turtles and Scooby Doo! Mystery Incorporated.
Combs stars with Andrew Divoff in the 2012 Screen Media Films release Night of the Living Dead 3D: Re-Animation, a prequel to the 2006 cult hit Night of the Living Dead 3D directed by Jeff Broadstreet.
On television, Combs enjoyed critical and popular success playing alien characters on the various modern Star Trek incarnations, beginning in 1994 with Star Trek: Deep Space Nine, in 2000 with Star Trek: Voyager, and in 2001 with Star Trek: Enterprise. Combs has played nine different onscreen roles in the Star Trek universe. His largest science-fiction role to date has been his regular guest role on Star Trek: Deep Space Nine as the Vorta clone Weyoun.
On the same series, Combs had a recurring role as the Ferengi character Brunt. During the DS9 episode "The Dogs of War", Combs appeared as both Weyoun and Brunt, making Trek history as the first actor to play two unrelated recurring roles on screen in the same episode.
On Star Trek: Enterprise, Combs had a recurring role as Shran, an Andorian military officer.
In addition to his recurring Star Trek roles, Combs had non-recurring roles as a human police officer Kevin Mulkahey, as the alien Tiron on Star Trek: Deep Space Nine; as the alien Penk on Star Trek: Voyager; and as the Ferengi pirate Krem on Star Trek: Enterprise. Along with many other actors, writers, and creators of the show, Combs also had a cameo appearance as a holographic patron in Vic's Lounge in the final episode of Star Trek: Deep Space Nine. Combs also voices the character of Romulan Commander Suldok for the Star Trek: Elite Force II video game.