From 2005 to 2009, Stamos had a starring role on the NBC medical drama ER as Dr. Tony Gates. In October 2009, he began playing the role of Albert in the Broadway revival of Bye Bye Birdie, which he played until January 2010. He then played Senator Cantwell in a Broadway revival of Gore Vidal's play The Best Man from July to September 2012, replacing Eric McCormack.
From September 2015 to 2016, Stamos starred as the lead character in the Fox sitcom Grandfathered. He executive produced the Netflix series Fuller House, in which he reprised the role of Jesse Katsopolis. He also starred in Never Too Young to Die (1986), Born to Ride (1991) and as Dr. Nicky in the Lifetime/Netflix psychological thriller You.