Cleary pulled up chasing his own kick soon 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.
He cut a forlorn figure in the sheds.
"He's pretty shattered, actually," coach and father Ivan Cleary said.
"Obviously I'm torn between his coach and his dad right now as well. It's very disappointing."
Cleary's setback continues a frustrating start to the year for the 26-year-old, 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.
His 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.
Cleary is the second Blues player to go down in the opening two games of the round after would-be NSW centre Tom Trbojevic also injured a hamstring in Manly's loss to the Dolphins.
The Penrith star, who would be an almost automatic selection as Blues halfback, will undergo scans on Saturday afternoon to determine the severity of the injury.
"He felt it straight away, so he knew. That would suggest it's decent (severity)," said coach Cleary.
Penrith's resolute defence withstood a stout challenge from the Bulldogs. (Mark Evans/AAP PHOTOS)
Cleary's 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 BlueBet Stadium.
Brian To'o was among the scorers in the Panthers' hard-fought win over a dogged Canterbury. (Mark Evans/AAP PHOTOS)
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.
Two late tries proved reward for Canterbury's effort, with Matt Burton scything past Paul Alamoti and Dylan Edwards before Jacob Kiraz slid over as the siren sounded.
Bulldogs coach Cameron Ciraldo applauded his side's ability to stay in a grind with the reigning premiers.
"We came here confident but I reckon we're leaving even more confident," he said.
"Physically, we're looking a lot better but we're still a work in progress. The more we play together, the more we train, the better we'll get."
A frustrated Burton found himself penalised for back-chatting referee Liam Kennedy in the final minutes, as referee dissent continues to prove a hot topic in the NRL.
5°C