He is best known for portraying Phil Coulson in films and television series set in the Marvel Cinematic Universe from 2008 to 2024.

He attended high school in Chapel Hill, North Carolina, where his father was a professor at nearby Duke University.

He worked various jobs, such as being a bar back, a security guard at the Guggenheim Museum, and a parking valet at a restaurant.

[5] He later enrolled at New York University's Tisch School of the Arts, where he studied drama and English, and graduated in 1986.

[6] Gregg was a founding member, and later artistic director, of the off-Broadway Atlantic Theater Company, which formed in 1983.

[6] He is the director and screenwriter of the 2008 film Choke, based on the Chuck Palahniuk novel of the same name, starring Sam Rockwell.

[10] Gregg noted his being a part of the expanding Marvel Cinematic Universe as being very exciting; "Agent Coulson was one of the guys who wasn't really in the comic books, and he was a very kind of small role in Iron Man," he said, "and I was just very lucky that they chose to expand that character and chose to put him more into the universe of it.

Gregg reprised his role as Agent Coulson in the 2019 superhero film Captain Marvel and the animated series What If...?, episodes "What If... the World Lost Its Mightiest Heroes?"

[20] Gregg married actress Jennifer Grey on July 21, 2001; the couple co-starred in the Lifetime TV movie Road to Christmas.