Duchene hurt his knee during the first shift in Saturday's 3-2 home win against the San Jose Sharks when he collided with teammate Jamie McGinn.
The 23-year-old leads the Avalanche with 70 points (23 goals) in 71 games this season.
The injury is a big blow for Colorado, which will return to the NHL playoffs for the first time since 2010.
Duchene was also on Canada’s Olympic gold medal winning team in Sochi in February.