Jeffrey 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, House on Haunted Hill, I Still Know What You Did Last Summer, and The Frighteners.

Combs has had numerous roles in science fiction television series. In addition to his more well known roles on "Star Trek: Deep Space Nine," he also starred as the telepath Harriman Gray, in "Eyes", a first season episode of Babylon 5, on The 4400 as Dr. Kevin Burkhoff, as Edgar Allan Poe in "The Black Cat", an episode of Masters of Horror. In July 2009, Combs returned to his stage roots and reprised his role as Edgar Allan Poe in a one-man theatrical show entitled Nevermore...an Evening with Edgar Allan Poe at The Steve Allen Theater in Hollywood, CA.