Leafs coach Randy Carlyle said Monday 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.
He 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 played 70 games in a season since 2008-09.
The Leafs have three road games left and are three points behind Columbus for the last playoff spot in the Eastern Conference.