Simmons was born in Detroit, Michigan, the son of Patricia, an administrator, and Donald William Simmons, a college professor. He has a brother, David (a singer and songwriter), and a sister, Elizabeth. He attended the University of Montana and was a member of the Seattle Repertory Theatre.

Prior to his film & television career, Simmons was a Broadway actor and singer. He was in the revival of Guys and Dolls as Benny Southstreet. He also played the role of Jigger in a revival of Carousel at the Houston Grand Opera.

Simmons is known for his TV roles as Dr. Emil Skoda, a police psychiatrist who has appeared on three of the four incarnations of Law & Order, and as the sadistic Vernon Schillinger on the prison drama Oz. He also played the obsessively egotistical newspaper editor J. Jonah Jameson in all three Spider-Man movies. Simmons provided his voice for two newspaper editors in two episodes of the eighteenth season of The Simpsons. The characters are never named, but are obviously meant to emulate the character of Jameson (one even demands "pictures of Spider-Man.") He also stars as Ralph Earnhardt, the father of famous race-car driver Dale Earnhardt, in 3: The Dale Earnhardt Story. Currently he plays as the Assistant Chief of the LAPD, Will Pope in The Closer.

Less well known is that Simmons provided the voice of the yellow M&M in the product's commercials as well as voiceover work for Norelco razors. He also provided the voice of General Wade Eiling in Justice League Unlimited. He also did an audio book for Tom Clancy's Net Force Point of Impact. Like many of his Law & Order co-stars, he also appeared in an episode of Homicide: Life on the Street, though he portrayed a criminal suspect rather than his Dr. Skoda character.