He came to prominence as a teen idol in the 1980s, appearing in teen and young adult film roles in The Outsiders (1983), Oxford Blues (1984), St. Lowe appeared as Robert Mc Callister on the ABC television drama Brothers & Sisters (2006–2010), followed by a four-year run as Chris Traeger on the NBC sitcom Parks and Recreation (2010–14), for which he was critically acclaimed. Ethan Willis on the CBS medical drama Code Black (2015–) and appears with his two sons, Matthew and John Owen, in the A&E reality series The Lowe Files (2017–).
Thereafter, his film career decreased and he ventured into television, making his breakthrough as Sam Seaborn on the NBC political drama The West Wing (1999–2003), for which he received a Primetime Emmy Award nomination and two Golden Globe Award nominations.
In his autobiography Stories I Only Tell My Friends, he wrote regarding Sheen, "We were both nerds [...] he wanted to be a baseball player." One of Lowe's earliest roles came in the 1983 TV film Thursday's Child, for which he received his first Golden Globe Award nomination for Best Supporting Actor in a Series, Miniseries, or Television Film.
His breakthrough role was his big screen debut in 1983, when he and Emilio Estevez were cast in Francis Ford Coppola's The Outsiders. Elmo's Fire, making them the two more prominent actors from the group known as the Brat Pack. followed, with Demi Moore (who had starred alongside Lowe in St. He then received his second Golden Globe Award nomination for Best Supporting Actor for his role as the mentally disabled Rory in Square Dance (1987).
After leaving the show, Lowe was the star and executive producer of a failed NBC drama, The Lyon's Den (2003). Although Lowe had expressed unhappiness about his decreased 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 once more with Sorkin, whose talents as a writer Lowe highly regards. Derek Shepherd of Grey's Anatomy, which eventually went to Patrick Dempsey.
He recalled meeting Paul Newman there, and that the older actor encouraged him to work in the theatre in 1993 when filming a British TV production of the Tennessee Williams play Suddenly, Last Summer with (the now) Dame Maggie Smith and Natasha Richardson.
In January 2007, ABC announced that Lowe would be staying on Brothers and Sisters as a "special guest star" for the rest of Season 1 after Lowe's initial appearance on the show in November 2006 brought the best ratings and demographic showing for the show since its premiere.
Soon after ABC announced an early Season 2 renewal for Brother & Sisters in March 2007, Lowe announced he would be returning for the show's second season.
In that same year, Lowe filmed his role as a movie agent in the 2006 independent film Thank You for Smoking.
In 2006 he filmed The Perfect Day for TNT, in which he took a pay cut to film in New Orleans in order to help the hurricane-ravaged area.