Bentancur suffered an anterior cruciate ligament damage against Leicester City on Saturday.
The Uruguay international opened the scoring in a game Tottenham will eventually go on to lose 4-1 but was forced off just after the hour mark following a challenge with Nampalys Mendy.
Bentancur has made 26 appearances for Tottenham across all competitions this season, scoring six goals and providing two assists.
A tweet from Tottenham read: "We can confirm that Rodrigo Bentancur has ruptured the anterior cruciate ligament in his left knee and will be out of action for the remainder of the campaign. He will undergo surgery before beginning his rehabilitation with our medical staff. We're all behind you, Rodrigo."
Bentancur will therefore miss Tottenham's Champions League trip to AC Milan on Tuesday.
Tottenham have also recently lost goalkeeper Hugo Lloris to injury while midfielders Pierre-Emile Hojbjerg is suspended and Yves Bissouma injured.
