In 1980, Harmon gained a regular role in the prime time soap opera Flamingo Road, in which he played Fielding Carlisle, the husband of Morgan Fairchild's character. Despite initially good ratings, the series was canceled after two seasons. Following its cancellation, he landed the role of Dr. Robert Caldwell on the prestigious NBC Emmy-winning series St. Elsewhere in 1983. Harmon appeared in the show for almost three seasons before leaving in early 1986 when his character contracted HIV through unprotected intercourse, one of the first instances where a major recurring television character contracted the virus (the character's subsequent off-screen death from AIDS would be mentioned two years later). In the mid-1980s, Harmon also became the spokesperson for Coors Regular beer, appearing in television commercials for them.[15]
Harmon's career reached several other high points in 1986. In January, he was named People magazine's Sexiest Man Alive. Following his departure from St. Elsewhere in February, he played the lead in the TV movies Prince of Bel Air, co-starring with Kirstie Alley, and The Deliberate Stranger, in which he portrayed the real-life law student turned cross-country serial killer Ted Bundy. With his career blossoming, he gained a role in the 1986 theatrical film Let's Get Harry and the lead role in the 1987 comedy Summer School, again co-starring with Kirstie Alley. Returning briefly to episodic television in 1987, Harmon had a limited engagement on the series Moonlighting, playing Cybill Shepherd's love interest Sam Crawford for four episodes. He then starred in the 1987 TV movie After The Promise. In 1988, he co-starred with Sean Connery and Meg Ryan in the 1988 feature film The Presidio, and also opposite Jodie Foster in the film Stealing Home. Despite several high-profile roles, Harmon's film career never gathered momentum and, after a muted reception to his 1989 comedy Worth Winning, he returned to television, appearing in various television movies.
Harmon's next regular television role would be as Chicago police detective Dickie Cobb for two seasons (1991–1993) on the NBC series Reasonable Doubts. In 1993, he appeared in one episode in the role of a rodeo clown on the CBS comedy/western series Harts of the West with future cast mate Sean Murray, who plays McGee on NCIS.
In 1995, Harmon starred in the ABC series Charlie Grace, in which he portrayed a private investigator. The series lasted only one season, after which he returned to ensemble medical shows on the series Chicago Hope, in which he played Dr. Jack McNeil from 1996-2000. He also portrayed astronaut Wally Schirra in one episode of the 1998 mini-series From the Earth to the Moon.
In May 2002, he portrayed Secret Service Special Agent Simon Donovan on The West Wing in a four-episode story arc. The role gained him his second Emmy Award nomination, exactly 25 years after his first nomination.[14] Harmon appeared in a guest starring role in two episodes of JAG in April 2003, which introduced the character of NCIS agent Leroy Jethro Gibbs; since 2003, Harmon has starred as Gibbs in the CBS drama NCIS. During his time on the show, he was reunited with three of his former Chicago Hope co-stars, Rocky Carroll, Lauren Holly, and Jayne Brook. Since 2008, he has also been a producer/executive producer. Also in 2003, Harmon had a supporting role in the remake of the comedy film Freaky Friday.
Harmon has also starred in several stage productions in Los Angeles and Toronto. At the Cast Theatre in Los Angeles he performed in Wrestlers and The Wager. In the late eighties he was