The 25-year-old midfielder, who is out of contract, has been a regular for the Grecians since his debut back in 2007 but has now penned a two-year deal at the Kassam with the option of a further year.
“First and foremost he is a very good player,” U’s boss Michael Appleton told the club’s official website.
“He is a terrific competitor, he links things together well and every time we’ve watched him he has caught the eye. He has a lot of experience for someone who is still only 25 and we think he will be a major asset to this football club.”
Sercombe added: “It’s exciting to be joining Oxford. I have been with Exeter since I was a kid so it was hard to leave but I know I have made the right decision. I wanted a new challenge and I’m really looking forward to being part of what Oxford are trying to build here.”
Exeter-born Sercombe becomes Oxford’s second signing in 24 hours following Kemar Roofe’s arrival.