Born to Charles Lowe and Barbara Hepler in Charlottesville, Virginia and raised in Dayton, Ohio, Lowe became famous after appearing in a string of popular movies that included other members of the Brat Pack, the most notable being St. Elmo's Fire. Lowe and his brother Chad Lowe grew up on the Westside of Los Angeles and attended Santa Monica High School, where one of their classmates was fellow brat-packer, Emilio Estevez. Today, Lowe makes his home with his wife and children in Montecito, California.

Lowe gained notoriety in 1988 after a video of him having sex with two women, one of whom was underage, became public. He had met the women at a bar while in Atlanta attending the 1988 Democratic National Convention, and later claimed that he didn't know one of them was underage, and that it was reasonable to assume that someone in a bar was of legal age. The video that was widely circulated was not the one with the underage girl and her lesbian hairdresser girlfriend but that of a threesome with a model called "Jennifer", a young friend called "Justin Morris" and the actor himself, shot in a hotel room in Paris. Lowe was sentenced to twenty hours of community service. He was later committed to a rehabilitation clinic for alcohol addiction.

He is perhaps best known for playing Sam Seaborn in the television show The West Wing, a role which was his from 1999 - 2003. When the show premiered, Lowe's character was to be much more important. But the extremely talented cast — including Allison Janney, Richard Schiff, Stockard Channing, Bradley Whitford, and Martin Sheen (who was only supposed to be a guest star) — soon made the show into the hottest ensemble drama on TV, and Sam Seaborn became possibly the character with the least screen time. Lowe left the show in a highly publicized exit during the fourth season. His exit was quickly followed by that of series creator and writer Aaron Sorkin, and director Thomas Schlamme - a move which saw the show's style change greatly, to mixed reactions from fans.

After leaving, he was star and executive producer of a failed NBC drama The Lyon's Den (2003). In 2004, he tried again in a series entitled Dr. Vegas, but it also was quickly cancelled.

In 2005 he starred as Lieutenant Daniel Kaffee in a London West End production of Sorkin's play A Few Good Men, the first time the two have worked together since The West Wing. Although Lowe had expressed unhappiness about his role on that show at the time of his departure, he has now repeatedly said that any animosity between them is over and that he was pleased to be working with Sorkin once more, whose talents as a writer he highly regards. The West Wing is ending soon and it has been confirmed that Rob Lowe will return for last episodes and reprise his role as Sam Seaborn .