Ferrer began his career in the early 1980s making guest appearances on episodic television. In 1983, he was given a small part as a waiter in The Man Who Wasn't There. He also had a small part in Star Trek III: The Search for Spock (1984) as the Excelsior helm officer. He had a major role in the 1987 action movie RoboCop as aspiring, cocaine-snorting corporate executive Bob Morton. Since then, Ferrer has been cast in many major movies, usually in the role of flamboyant villains with a sense of humour. Ferrer's notable screen roles include a sinister biker in Valentino Returns (1988), an engineer in DeepStar Six (1989), Commander Arvid Harbinger in the comedy Hot Shots! Part Deux (1993), Lloyd Henreid in the Stephen King mini series The Stand (1994), investigative reporter Richard Dees in Stephen King's The Night Flier (1997), and Eduardo Ruiz in Traffic (2000).
In the early 1990s, Ferrer appeared on three primetime TV series simultaneously: as D.A. Todd Spurrier in Shannon's Deal (1989–1991), as Cajun cop Beau Jack Bowman in Broken Badges (1990–1991), and as cynical, wittily abrasive FBI forensics specialist Albert Rosenfield in Twin Peaks (1990–91). Ferrer reprised the role of Albert in the movie Twin Peaks: Fire Walk with Me (1992). He played another medical examiner on the small screen, Dr. Garret Macy, in the television crime/drama series Crossing Jordan (2001–07).
Ferrer performed as the voice of the Heretic leader in the video game Halo 2, as well as the protagonist, Jack, in the video game BioShock. In 1999, at the 41st Grammy Awards, he was nominated for "Best Spoken Word Album for Children" in Disney's The Lion King II, "Simba's Pride Read-Along". In 2003, Ferrer made his New York stage debut in the off-Broadway production of The Exonerated.
Ferrer played a supervillain called The Weatherman in the failed 1997 TV pilot, Justice League of America. Later in the year, Ferrer provided the voice for a similar character, Weather Wizard, in the Superman: The Animated Series episode "Speed Demons". Ferrer also voiced Aquaman in another Superman: Animated episode, "A Fish Story". Ferrer has also provided voice-over roles in the TV series Robot Chicken (2006) and American Dad! (2007).
He co-created and co-wrote various comic books with Jenerators band member Bill Mumy, including Comet Man, The Dreamweaver, and Trypto the Acid Dog (released by Dark Horse Comics).
Ferrer played Jonas Bledsoe on NBC's short-lived update of the Bionic Woman series. Ferrer also starred in another short-lived NBC series, Kings, in 2009 as a military commander of Gath. He played Los Angeles Police Lieutenant Felix Valdez in the 2011 Lifetime police procedural drama, The Protector. Also in 2011 he started a multiple episode guest role on the final season of Desperate Housewives.