During his run on Thirtysomething, People magazine named him one of the "50 Most Beautiful People". Horton acted in television shows including St. Elsewhere, The White Shadow, Dallas, Eight Is Enough, "In Treatment" and The Geena Davis Show, played the lead in the short-lived series Brimstone, and played Crane McFadden in the one season series (1982–1983) "Seven Brides for Seven Brothers". He played Jacob in the 1982 feature film Split Image, Father Mahoney in the 1986 feature film "Where the River Runs Black" Roy Fox in the 1996 film "Two Days In The Valley" and played Burt in the 1984 Stephen King movie Children of the Corn. He had a minor role in Cameron Crowe's Seattle romantic comedy, Singles. He played Harry Landers in the "Hospital" skit from Amazon Women on the Moon opposite wife Michelle Pfeiffer, whom he had previously directed in the ABC Afterschool Special One Too Many in 1985.
Horton also appeared in the 1997 TV movie version of the Jon Krakauer book Into Thin Air: Death on Everest, playing Scott Fischer, the leader of the disastrous 1996 climb on Mount Everest. He was also in the movie Sideout (1990) as Zach Barnes, a down and out ex-volleyball champ. As a director he has worked on several television series including The Shield, Thirtysomething, The Wonder Years, Once and Again, and directed the pilot for Grey's Anatomy as well as pilots for Class of '96, Birdland, Dirty Sexy Money, The Philanthropist and Reconstruction. He directed the 1990 film for television Extreme Close-up as well as the 1995 feature film The Cure. As a producer he produced Reconstruction (which he co-created), Lone Star, The Philanthropist, The Body Politic (which he also co-created), Grey's Anatomy, Six Degrees and Murder Live (for which he wrote the story). He appeared in Who Killed the Electric Car? and is on the board of directors of the Environmental Alliance. As of 2010 Horton is an executive producer and director of Grey's Anatomy on ABC, and produces and directs NBC's The Philanthropist.