Cleary pulled up chasing his own kick in the minutes before halftime on Friday night and flagged his injury with Panthers trainer Shane Elford. Penrith's co-captain left soon after, replaced in the halves by young gun Jack Cole.
The setback continues a frustrating start to the year for Cleary, who missed a month with the injury to his right hamstring earlier in the season and was rested last week, only one match after making his comeback.
Cleary's departure was the last thing NSW coach Michael Maguire needed as he faces a dearth of strong halves options for the Origin opener on June 5.
The Penrith star, who would be an almost automatic selection as Blues halfback, will go for scans over the weekend to determine the severity of the injury.
His misfortune could open the door for Cronulla playmaker Nicho Hynes to start at halfback for NSW, with Parramatta's Mitch Moses facing his own race against time to recover from a foot fracture.
For the Panthers, young playmaker Cole is poised for a stint starting in the halves after Cleary's usual understudy Brad Schneider suffered a knee injury playing NSW Cup on Friday.
Cleary's injury occurred late in a hotly-contested first half, and only minutes before Brian To'o crushed the Bulldogs' spirits by scoring 90 seconds out from the break.
The score was 12-0 at halftime but the Bulldogs were the more enterprising side early as captain Stephen Crichton made his highly-anticipated return to the Panthers.
Penrith were rusty early on in the wet conditions, a recurrent problem for the reigning premiers, and while the Bulldogs were willing to chance their arm down the edges, they could not land the final punch.
A day after Penrith missed out on signing David Fifita, Luke Garner did his best impression of the barnstorming Queensland second-rower by barging through six defenders and scoring first on the left edge. It had taken 25 minutes for the game's first points.
As Cleary's injury cast a shadow over the contest, Matt Burton scythed past Paul Alamoti and Dylan Edwards on the fifth tackle to give the Bulldogs hope as the final 10 minutes approached.
With the game slipping away, a frustrated Burton found himself penalised for back-chatting referee Liam Kennedy, but Jacob Kiraz's four-pointer in the final seconds at least kept the scoreline close.
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