The 25-year-old, who spent a loan spell with the U's back in 2007/08, was on loan at Aldershot last season, making 37 appearances in League Two.
He signed a two-year deal with the U's with an option for a further year having passed a medical.
"It's a club I have always followed since my first time here," Rose told the club's official website. "They gave me my big break and I am so pleased to be back.
"I feel like I have matured as a player; I was only 19 when I first signed, and I believe I have learned my trade in the years in between.
"There is such potential here and as soon as I heard of Oxford's interest there was only one club I wanted to play for."