The Panthers confirmed the NSW five-eighth had suffered a grade-two medial ligament tear during Saturday's get-out-of-jail win over the Gold Coast.
The club said he had been sidelined indefinitely and would not be back for the final three regular rounds.
He is now eyeing Week One of the finals as his earliest possible return.
Medial ligament strains generally take 3-6 weeks to heal, meaning he may not be back at all this year, should the Panthers go out in straight sets in the finals.
Maloney has looked hindered over the past several weeks, playing with a toe injury and broken thumb.
He was criticised after missing 12 tackles and making just nine against Canberra in Round 21.
The Panthers have endured a torrid week, after the sacking of coach Anthony Griffin.
They've looked far from in peak form over the last month, flogged by Brisbane, and forced to overcome big deficits in their last three victories over Manly, Canberra and Gold Coast.
With Tyrone May shaping as Maloney's likely replacement, much of the pressure will be on 20-year-old halfback Nathan Cleary to steer the team around the park.
The Panthers go into Round 23 in fourth, but are equal with a resurgent Cronulla and a dangerous Warriors outfit on 28 points.
They also have a difficult draw, facing Newcastle, Warriors and Melbourne over the final three rounds.