Annable was born and raised in Suffern, New York. He attended Suffern High School, where he played basketball and baseball. He then attended Cornell University, where he majored in English and was a member of the Cornell Big Red men's basketball team. After graduating from college, Annable moved to Los Angeles to pursue an acting career.
Annable made his television debut in 2002, with a guest-starring role on the sitcom Reba. He then had a recurring role on the soap opera All My Children from 2002 to 2003. In 2004, Annable landed his breakout role as Justin Walker on the ABC drama Brothers & Sisters. The show was a critical and commercial success, and it ran for five seasons.
After Brothers & Sisters ended, Annable had leading roles in the short-lived comedy-drama What About Brian and the drama Red Band Society. He has also appeared in the films Little Black Book (2004), The Prince and Me (2004), Fired Up! (2009), and Kill Katie Malone (2010).
Annable is married to actress Odette Annable. The couple have one child, a daughter born in 2015.