Busfield was born June 12, 1957, in Lansing, Michigan, the son of drama professor Roger and secretary Jean Busfield. He graduated from East Lansing High School in 1975. He landed his first professional acting job at 18 in a children’s theater adaptation of Shakespeare’s A Midsummer Night’s Dream. Busfield studied drama at East Tennessee State University and traveled frequently with the Actors Theater of Louisville, which took him to Europe and Israel. In 1981, he moved to New York City, NY, where he joined the Circle Repertory Company for their production of Lanford Wilson’s Talley and Son. That same year, he landed his first film role with a bit part as a mortar-bearing soldier in the comedy classic, Stripes (1981).

More stage work followed, including a stint as understudy to Matthew Broderick in Brighton Beach Memoirs in 1982. The following year, Busfield relocated to Los Angeles to join the cast of Reggie (ABC, 1983), a short-lived comedy based on the British television series The Fall and Rise of Reginald Perrin (BBC, 1976–79). The year 1984 proved to be a busy one for Busfield; not only did he land his first substantial film role as Arnold Poindexter, the goofiest of the geek fraternity brothers in the hit comedy Revenge of the Nerds (1984) and its 1987 sequel, but he joined the cast of the long-running drama Trapper John, M.D. (CBS, 1979-1986), starring as the son of Pernell Roberts’ Trapper John McIntyre. He held the role until the series’ conclusion in 1986.

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.

Busfield had remained exceptionally busy during his thirtysomething stint, appearing as the nominal villain in the popular Kevin Costner fantasy Field of Dreams in 1989, and in 1990, replacing Tom Hulce as the lead in A Few Good Men, a smash Broadway production written by Aaron Sorkin, with whom he would later enjoy fruitful collaborations. He also made his directorial debut with a 1990 episode of thirtysomething, and would helm three episodes of the series before it ran its course. Roles in television features and theatrical films followed, including supporting turns in Sneakers (1992), Quiz Show (1994) and the likable kids’ fantasy Little Big League (1994), which allowed Busfield to show off his baseball skills as the first baseman for the Minnesota Twins (an avowed baseball fan, Busfield occasionally served as pitcher in several minor league games). His character, Lou Collins, was loosely based on Twins legend Kent Hrbek. Hrbek would serve as a consultant on the film and he and Busfield became friends.

Following the demise of Trapper John, he joined forces with his brother Buck to create the Fantasy Theatre, a professional touring company for children’s audiences – and later Honorary State Children’s Theater for California – based in his new hometown of Sacramento, CA. The Busfields also established the award-winning B Street Theater there in 1992, which was devoted to more adult productions. The following year, Busfield was cast as Elliot on thirtysomething. The part was his first mature role to date, and the producers requested that he grow a beard to help sell his image as a married man and father. Over the course of the hit Yuppie show’s three-season run, Elliot came to personify the best and worst aspects of the series: a successful advertising executive and father, Elliot also infuriated his friends and family (and viewers) with his marital infidelity and competitive streak with partner Michael Steadman (Ken Olin), all of which went on while his wife Nancy (Patricia Wettig) struggled with ovarian cancer. Despite his character’s unpleasant tendencies, Busfield brought humor and honesty to the role, and was nominated three times for an Emmy before winning one in 1991, shortly before conflicts between the producers and cast brought the show to an abrupt conclusion.

Busfield kept a foot on both sides of the camera from 2000 on; directing and executive producing the successful CBS drama Without a Trace (2002-) and appearing occasionally as the wheelchair-bound divorce attorney for Anthony LaPaglia’s Jack Malone. He also directed episodes of Las Vegas (NBC, 2003-), Damages (FX, 2007- ), and Studio 60 on the Sunset Strip. On the latter, he also co-starred on the short-lived Aaron Sorkin series as Cal Shanley, the occasionally nerve-plagued control director for the program’s self-titled show-within-a-show. Though that show was ultimately cancelled, despite much marketing as the “next big thing,” in 2007, Busfield moved on, serving as executive producer of the Brooke Shields-led drama, Lipstick Jungle (NBC, 2008-2009).

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 resided in Howell, Michigan, from 2013 to 2018 but moved to New York City late in 2018. During the 2016–17 academic year, Busfield served as an artist in residence at Michigan State University.

In 2019, Guest Artist, directed by Busfield, premiered at the Santa Barbara International Film Festival. The film is written by, and stars Jeff Daniels. Guest Artist was shot on location in New York City, and in Daniels’ hometown of Chelsea, MI. This film marks the launch of Grand River Productions, a production company with Daniels, Busfield, and Melissa Gilbert.