Leafs coach Randy Carlyle said at Monday's practice that Lupul will undergo a meniscus procedure and the recovery time is expected to be three weeks.
Lupul was a scratch for Toronto's win over Boston on Thursday, and played limited minutes in the Leafs' loss to the Jets on Saturday.
The Fort Saskatchewan, Alta., native has 22 goals and 22 assists in 69 games this season.
Lupul is a proven scorer when healthy, but has battled injuries throughout his career. He hasn't reached 70 games played in a season since 2008-09, when he suited up for 79 with Philadelphia.
The Leafs have three road games left this season and are three points back of Columbus for the last playoff spot in the Eastern Conference.