Edwards was born in Santa Barbara, California, the son of Erika Kem (née Weber), an artist/landscape painter, and Peter Edwards, an architect. He has two older sisters, Heidi and Ann-Marie, and two older brothers, Peter and Jeffrey. Edwards was encouraged by his parents to attend college before pursuing his interest in acting. He received a scholarship to the Royal Academy of Dramatic Arts in England and studied theatre at University of Southern California but by the age of nineteen was being offered enough acting work to enable him to leave college.
Edwards' early work included a co-starring role in the TV series It Takes Two with Richard Crenna and Patty Duke Astin as his parents and Helen Hunt as his sister. He made a cameo in the hit 1982 film Fast Times at Ridgemont High as "Stoner Bud". In 1984, he starred in the hit comedy film Revenge of the Nerds playing the main role of Gilbert Lowe, a sensitive and well meaning nerd, Lewis' (played by Robert Carradine) best friend and later president of the Tri-Lambs. He reprised the role of Gilbert for a few brief scenes in the sequel Revenge of the Nerds II: Nerds in Paradise (1987), with his character unable to join the rest of the nerds because of a broken leg.
It was Edwards' role as LTJG Nick "Goose" Bradshaw alongside Tom Cruise in the 1986 film Top Gun that brought his first widespread public acknowledgement. His character, who died in an aviation accident, was among the most prominent and popular in the film. He appeared as a terminally ill patient in Hawks (1988) alongside Timothy Dalton, another role which brought him worldwide fame. He starred in the Cold War era comedy Gotcha! as a college student who gets wrapped up in spy antics. He starred in the 1990 movie Downtown with Penelope Ann Miller and Forest Whitaker. He also played widowed veterinarian Chase Matthews, father of Edward Furlong's character, in the horror film Pet Sematary Two (1992), a sequel to the film Pet Sematary in 1989. In 1992 and 1993 he played Mike Monroe in ten episodes of Northern Exposure.
Edwards' best known role is as Dr. Mark Greene on the long-running TV series ER, whom he portrayed from its premiere in 1994 to the end of the 8th season in 2002. The series also afforded Edwards his first opportunity to direct. Edwards' desire to pursue directing led to his request to be written out of the series. He reportedly earned $35 million for three seasons on ER, which made him one of television's highest-paid actors. Edwards and his co-star George Clooney were the ones who suggested doing an episode of ER live. The fourth-season premiere, "Ambush", was performed live twice, with an East Coast and a West Coast version.
Edwards has not won a Primetime Emmy, though he has been nominated four times. He won a Golden Globe Award For Best Performance by an Actor-In a TV Series after being nominated four times, and he has two Screen Actor's Guild Awards.
In 2007, Edwards appeared as SFPD inspector Bill Armstrong in David Fincher's Zodiac, about the Zodiac Killer, the notorious serial killer who terrorized San Francisco in the 1960s and 1970s.
In 2008, Edwards returned to ER to reprise his role as Dr. Greene (in flashback scenes, where he treats the dying son of character Catherine Banfield) for one episode during its 15th and final season.
In 2010, Edwards appeared in the movie Motherhood, which set a record for the biggest bomb in British cinema history by garnering £88 on 11 tickets on opening weekend. Motherhood did not fare much better in the United States. earning $93,388 in three weeks of release.
In 2013, Edwards returned to episodic television with the conspiracy drama Zero Hour, playing the male lead Hank Galliston. After three episodes, Zero Hour was cancelled due to poor ratings.
Edwards was the voice of Echo, one of the fighter jets, in the Disneytoon Studios film Planes, and also voiced the character Pegleg Pirate in an episode of Blaze and the Monster Machines.
Edwards served as the director of the 2016 film My Dead Boyfriend.
Since 1994 Edwards has been married to Jeanine Lobell. They have one son and three daughters. They reside in New York City. In 1994, Lobell, who had worked as a makeup artist, founded the Stila cosmetics line, which she then sold to Estee Lauder in 1999.
Edwards serves as chairman for Shoe4Africa, a non-profit organization that donates shoes to Kenyan athletes and aims to build the largest public children's hospital in Africa. He ran in the ING New York City Marathon on November 1, 2009 to raise funds for Shoe4Africa.
Since his teenage years, Edwards has been a close friend of picture book illustrator Steven Kellogg. In 2011, Edwards's gift of $350,000 made it possible for Kellogg's complete life's work of more than 2700 illustrations to be donated to the Mazza Museum of International Art from Picture Books.
Edwards has been a certified private pilot (airplane single engine land) since 2012.
Edwards received four Emmy nominations for Outstanding Lead Actor in a Drama Series. He earned a People's Choice Award for Favorite Male Performer in a New Television Series (1995); and won six Screen Actors Guild Awards for: Outstanding Performance by a Male Actor in a Drama Series (1996 and 1998), and Best Ensemble Cast (1996, 1997, 1998 and 1999). He won the Golden Globe Award for Best Performance by an Actor in a Television Drama in 1998).
Edwards also won a Daytime Emmy for the production of the underground rock documentary N.Y.H.C. (1999) and the telepic adaptation of Kimberly Willis Holt's 1998 coming of age novel My Louisiana Sky (2001), and earned the Carnegie Medal Award for: My Louisiana Sky (2003).