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.
He also appeared on The Tonight Show with Conan O'Brien.
Lowe is currently teaming up with 44 Blue to produce a reality series entitled Potomac Fever about young adults living in Washington, D. In 2011, Lowe guest starred in a recurring role on Showtime's comedy Californication.
In 2006, it was announced that Lowe would join the cast of Brothers & Sisters for a guest run of several episodes.
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.
During the final season of The West Wing, Lowe returned to his role of Sam Seaborn, appearing in two of the final four episodes.
In 2011, Lowe appeared on The Oprah Winfrey Show and stated that he left the show because he did not feel he was being respected, when the other lead characters received a raise and he did not. 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 had worked together since The West Wing.