Busfield was born in Lansing, Michigan, the son of drama professor Roger and secretary Jean Busfield.
In 1981, Busfield had a small part in the hit comedy Stripes with Bill Murray and Harold Ramis. He plays a mortar gunner on the practice range.
In 1984, Busfield landed his first major film role as Arnold Poindexter in Revenge of the Nerds. He reprised the role in the 1987 sequel to that film, Revenge of the Nerds II: Nerds in Paradise.
Busfield's first television series was Trapper John, M.D., in which he played the physician son of the title character. Immediately prior to being cast on the 1980s series thirtysomething, he was still often playing teenagers and young adults, and the producers of the show asked him to grow his beard so he'd look old enough for the role. He would win an Emmy Award for this role. Later he was cast in the lead of other series, although none have lasted very long. Produced by Steven Spielberg, The Byrds of Paradise with Arlo Guthrie may be the most memorable for its setting in Hawaii and its offbeat characters.
In a 1987 episode of Matlock "The Rat Pack," he played a feature role. After appearing in Sneakers (1992) starring Robert Redford and Sidney Poitier, Busfield went to London in 1993 to make the television film Wall Of Silence, in which he played Ephraim Lipshitz, a Mossad agent infiltrating a community of Hasidic Jews. Also in that year, he starred in the film The Skateboard Kid.
In 1994, Busfield starred in the film Little Big League. Other film appearances include Sneakers (1992), Field of Dreams (1989) with Kevin Costner, and First Kid (1996) with comedian Sinbad.
In 1997, Busfield starred in the Canadian television film Trucks.
Recurring television roles include White House correspondent Danny Concannon on The West Wing; and the title character's incorrigible brother on the sitcom Ed, a show on which he was a co-executive producer and supervising producer.
Busfield also dabbles in directing television and has directed multiple episodes of thirtysomething, Without a Trace (on which he appeared as a divorce lawyer, in a wheelchair, for Jack Malone), and the Sorkin/Schlamme predecessor to The West Wing, Sports Night.
Beginning in September 2006, Busfield was a regular on the short lived Sorkin/Schlamme series, Studio 60 on the Sunset Strip, where he played Cal Shanley, the fictional show's director. He also directed 6 episodes. After Studio 60, he continued to direct episodes of Las Vegas. He has also appeared in various episodes of Entourage playing himself, directing the fictional series Five Towns.
He guest starred in the 2010 Law & Order episode, "Brilliant Disguise" and in the 2011 Law & Order: Special Victims Unit episode "Russian Brides".
Busfield remains a stage actor and director whose Broadway credits include A Few Good Men and Brighton Beach Memoirs, where he was star Matthew Broderick's understudy. Off-Broadway, he worked with Circle Repertory Company in 1982. With elder brother Buck Busfield, he is co-founder of the B Street Theater in Sacramento, California, where he has appeared in and directed numerous contemporary works. The Busfield brothers also established Fantasy Theater, a touring troupe that plays to children. Busfield writes children's plays for the Fantasy troupe.
Busfield was married to actress and director Radha Delamarter before divorcing in 1986. The couple had a son, Willy. In 1988 he married fashion designer Jennifer Merwin, with whom he had children Daisy and Samuel. They filed for divorce in 2007.
A representative for Busfield said in January 2013 that Busfield had become engaged to actress Melissa Gilbert over the holiday season. They were married April 24, 2013 in a private ceremony at San Ysidro Ranch in Santa Barbara, California. Busfield and Gilbert now reside in Howell, Michigan.As actor
Sports Night (1998–2000)
Without a Trace (2002–2009)
Las Vegas (2003–2004; 2007–2008)
Studio 60 on the Sunset Strip (2006–2007)
Lipstick Jungle (2008)
Lie to Me (2009)
White Collar (2009)
The Deep End (2010)
The Glades (2010)
No Ordinary Family (2010)
Franklin & Bash (2012)
The Fosters (2013)
Childrens Hospital (2013)
Secrets and Lies (2015)
The Night Shift (2015–2016)
Second Chance (2016)
This Is Us (2017)