Jaglom was born to a Jewish family in London, England, the son of Marie (née Stadthagen) and Simon M. Jaglom, who worked in the import-export Business. His father was from a wealthy family from Russia and his mother was from Germany. They left for England because of the Nazi regime. Through his mother, he is a descendant of Philosopher Moses Mendelssohn. Jaglom trained with Lee Strasberg at the Actors Studio in New York, where he acted, wrote and directed off-Broadway theater and cabaret before settling in Hollywood in the late 1960s. Under contract to Columbia Pictures, Jaglom featured in such TV series as Gidget and The Flying Nun and acted in a number of films which included Richard Rush's Psych-Out (1968), Boris Sagal's The Thousand Plane Raid (1969), Jack Nicholson's Drive, He Said (1971), Dennis Hopper's The Last Movie (1971), Maurice Dugowson's Lily, aime-moi (1975) and Orson Welles' never-completed The Other Side of the Wind.

Jaglom's transition from acting in films to creating them was largely influenced by his experience watching the Italian film 8½ (1963), he told Robert K. Elder in an interview for The Film That Changed My Life.

Jaglom began his filmmaking career working with Jack Nicholson on the editing of Hopper's Easy Rider (1969), and made his writing/directing debut with A Safe Place (1971), starring Tuesday Weld, Nicholson and Welles. His next film, Tracks (1976), starred Hopper and was one of the earliest movies to explore the psychological cost on America of the Vietnam War. His third film, the first to be a commercial success, was Sitting Ducks (1980), a comic romp that co-starred Zack Norman with Jaglom's brother Michael Emil. Film critic David Thomson said of Jaglom's Can She Bake a Cherry Pie? (1983) that it "is an actors' film in that it grows out of their personalities—it is as loose and unexpected as life, but is shaped and witty as a great short story. In truth, a new kind of film." It stars Karen Black.

As a Playwright, has written four plays that have been successfully performed on Los Angeles stages: The Waiting Room (1974), A Safe Place (2003), Always—But Not Forever (2007) and Just 45 Minutes from Broadway (2009/2010). Jaglom is the subject of the Henry Alex Rubin's and Jeremy Workman's documentary Who Is Henry Jaglom? (1997).

In 1983, Jaglom taped lunch conversations with Orson Welles at Los Angeles's Ma Maison. Edited transcripts of these sessions appear in Peter Biskind's book My Lunches With Orson: Conversations Between Henry Jaglom and Orson Welles (2013).

In 1990, Jaglom directed Eating (1990) about a group of women with eating disorders and how they cope with it and one another. Babyfever (1995) was about the issue of women with ticking biological clocks. Last Summer in the Hamptons (1996) was a Chekhovian look at the life of a theatrical family and starred Viveca Lindfors in her last screen role. Déjà Vu (1997) was about the yearning of people trying to find their perfect soul mate and was the only film in which Vanessa Redgrave and her mother, Rachel Kempson, appeared together. Festival in Cannes (2002) explored the lives and relationships of those involved in the world of filmmaking and was shot entirely at the Cannes International Film Festival. Going Shopping (2005) explored that subject as the third part of Jaglom's "Women's Trilogy", the others being Eating and Babyfever.

Hollywood Dreams (2007) dealt with a young woman's obsession with fame in the film industry and introduced Tanna Frederick, who then starred in Jaglom's Irene in Time (2009), a look at the complex relationships between fathers and daughters, and Queen of the Lot, the sequel-of-sorts to Hollywood Dreams that co-starred Noah Wyle as well as Christopher Rydell, Peter Bogdanovich, Jack Heller, Mary Crosby, Kathryn Crosby and Dennis Christopher.

Jaglom's screen adaptation of Just 45 Minutes from Broadway, starring Frederick and Judd Nelson, was released in 2012. He is currently editing The 'M Word, which stars Frederick, Frances Fisher, Michael Imperioli, Gregory Harrison and Corey Feldman for a Fall, 2013 Theatrical Release.

Jaglom co-starred in four of his most personal films—Always, But Not Forever (1985), Someone to Love (1987) starring Orson Welles in his final film performance, New Year's Day (1989), which introduced David Duchovny, and Venice/Venice (1992) opposite French star Nelly Alard.