Ryan McPartlin graduated from the University of Illinois at Urbana-Champaign, with a degree in speech communication. During his years there he played for the Illinois Fighting Illini football team. He decided to pursue an acting career after spending time in Australia and New Zealand.
After getting a start as a model, McPartlin made his on-screen debut as a bit player during an episode of The Nanny. His first major role was in the daytime soap Passions, taking over from Dalton James as Hank Bennett from 2001 to 2004.
In 2005, McPartlin reunited with Fran Drescher in the comedy series Living with Fran, where he played her character's much younger boyfriend. Shortly after the program was cancelled, he unsuccessfully auditioned for the title role in the film Superman Returns. In 2007, he took a recurring role on NBC's Chuck, appearing as Devon "Captain Awesome" Woodcomb: he was promoted to a series regular in the second season.
McPartlin is currently married with actress Danielle Kirlin, with whom he has two sons.