Spurs have confirmed that Perisic, 34, picked up the injury during “non-contact training” and will undergo surgery before spending a number of months on the sidelines.
Perisic’s current contract expires at the end of the season so may have played his final game for the club.
A club statement read: “We can confirm that Ivan Perisic has suffered a complex Anterior Cruciate Ligament (ACL) injury in his right knee.
“The experienced Croatia international sustained the injury in non-contact training and will undergo surgery.
“Ivan will then commence his rehabilitation with our medical staff and is expected to be sidelined for the remainder of the season.”
Perisic has featured in every game under new manager Ange Postecoglou and impressed last time out as Spurs came from behind to beat Sheffield United with two goals in injury time, assisting Richarlison’s equaliser.