In a potentially-defining moment of the finals series, Newcastle hooker Phoenix Crossland was sent off for the hip-drop tackle which left Cleary injured in the 36th minute.
The decision left the Knights to play with 12 men for the final 44 minutes of Sunday's preliminary final, with Penrith taking an 8-6 lead from the penalty.
But the blow to Penrith's premiership hopes and chances of beating the Sydney Roosters if they win the preliminary final is massive.
Cleary had already been in doubt for Sunday's match with bone damage in his right foot, and was held back to come off the bench against Newcastle.
He came onto the field in the 25th minute after stalking the sideline for the opening stages, waiting for his chance to enter the fray.
But the stress injury in his foot is now the least of Cleary's concern, with the superstar No.7 now also set to miss the World Cup.
Penrith officials immediately identified a compound fracture of Cleary's left ankle, with the foot pointing the wrong way as he lay distraught on the ground.
Referee Gerard Sutton's decision to send Crossland off made the Knights hooker the first player to be marched for a hip-drop tackle in the NRL.
"Initially he's up high, he makes a definite action to twist," Sutton told Crossland and Knights captain Kalyn Ponga.Â
"He comes down on the leg with weight. There's extreme risk of serious injury. You're off."
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