Dunne began his professional acting career at age 19 with a small supporting role in The Other Side of the Mountain in 1975. He has since appeared on both film and television, starring in An American Werewolf in London (1981) as Jack Goodman, Johnny Dangerously (1984) as Tommy Kelly, After Hours (1985) as Paul Hackett, Who’s That Girl (1987) as Loudon Trott opposite Madonna, My Girl (1991) as Jake Bixler, Quiz Show (1994) as the Geritol Account Executive, Game 6 (2005) as Elliott Litvak, and I Like It Like That (1994) as Stephen Price. Dunne also played Dr. Vass, opposite Matthew McConaughey, in the Oscar-nominated 2013 film Dallas Buyers Club.

Dunne was born Thomas Griffin Dunne in New York City, the son of Ellen Beatriz (née Griffin) and Dominick Dunne. He is the older brother of Alexander and Dominique Dunne. His mother founded the victims’ rights organization Justice for Homicide Victims after Dominique’s murder in 1982. His father was a producer, writer, and actor. He is also the nephew of writers John Gregory Dunne and Joan Didion. Raised in Los Angeles, Dunne attended the Fay School in Southborough, Massachusetts and then went to Fountain Valley school in Colorado Springs, Colorado where he developed an interest in acting, appearing in many school plays. He was scheduled to perform in a school production of Othello when on the eve of a performance, Dunne was found smoking marijuana by a teacher. He was immediately expelled and soon after, he moved back to New York to pursue his acting interests. He studied acting at HB Studio in New York City.

From 1989 to 1995, he was married to American actress Carey Lowell, with whom he has one daughter, actress Hannah Dunne.

In 1995, Griffin Dunne was nominated for an Academy Award for Best Live Action Short Film for Duke of Groove, which he directed and co-wrote. He shared the nomination with producer Thom Colwell. Along with his producing partner, actress/producer Amy Robinson, he has produced several films including Baby It’s You, After Hours, Running on Empty and Game 6 through their company, Double Play Productions.

In July 2009, he married his second wife, Anna Bingemann, an Australian stylist.

Dunne’s TV appearances include Frasier (pilot episode “The Good Son” as caller Russell, season 3 episode 11 “The Friend” as Bob), Saturday Night Live, Alias, and Law & Order: Criminal Intent (Episodes 5, 118, and 128). He portrayed Tony Mink in the comedy Trust Me on TNT. In 2012, Dunne guest-starred as management consultant Marco Pelios in seven episodes of the premiere season of the Showtime TV series House of Lies.

In 2018 he joined the cast of This is Us where he currently stars as Nicky Pearson, Jack Pearson’s brother.