The Brazilian was forced off in the 3-0 Premier League triumph over Stoke City on Sunday, following a robust challenge from Charlie Adam.
Paulinho subsequently underwent a scan on the injury, and will be unavailable for new manager Tim Sherwood for at least the next four weeks.
A statement on the club's official website confirmed: "Following an MRI scan, the club can confirm that Paulinho has sustained significant ligament damage to his right ankle from Charlie Adam during Sunday's win against Stoke City.
"The Brazil international was forced off as result of the injury and is expected to be sidelined for at least four weeks."
Paulinho joined the White Hart Lane outfit in the close-season, and has become an established member of Tottenham's midfield with 17 Premier League appearances so far this season.
He will miss the trip to reigning champions Manchester United on New Year's Day, and could also be absent for fixtures against Crystal Palace, Swansea and Manchester City - as well as the FA Cup third-round meeting with London rivals Arsenal.
