Also injured over the weekend, North Queensland forward Griffin Neame is set to miss two months after fracturing the cricoid cartilage in his throat, while Warriors playmaker Te Maire Martin will need two months out to recover from a leg injury.
Brailey left the field following a tackle midway through the second half of the Knights' 34-24 win on Sunday with what was initially thought to be a meniscus injury to his right knee.
Scans confirmed a graver prognosis for Brailey, who has not only torn his meniscus, but faces surgery on the same ACL he injured in 2020.
Newcastle released a statement pledging to "continue to support our inspirational co-captain" in his recovery.
Brailey's knee problem is the latest in a string of injury blows for the improved Knights this season, with Kalyn Ponga, Tyson Frizell, Adam Elliott, Tyson Gamble, Kurt Mann and Simi Sasagi among the players to have spent time in the casualty ward through six rounds.
Mann and Phoenix Crossland are set to share Brailey's duties for Saturday's game against Penrith.
Utility Mann played hooker late in the 2020 season when Brailey went down with his previous ACL injury, while Crossland started there in round three after a concussion ruled out the co-captain.
"Having Tyson Gamble come back will allow Phoenix and Kurt to rotate through that No.9 spot. It will take two of them to cover Brails in the middle," Newcastle coach Adam O'Brien said after the Warriors game.
O'Brien also indicated Greg Marzhew and Dom Young would remain his first-choice wingers despite Hymel Hunt, who started in round one, recovering from injury in time to face the Panthers. In Brailey and Ponga's absence, Frizell will captain the Knights.
Warriors five-eighth Martin left the field just after halftime at McDonald Jones Stadium, fracturing his left fibula in a tackle.
The club confirmed on Tuesday that he would miss eight weeks and be replaced by Dylan Walker in the halves against North Queensland this weekend.
In Townsville, the struggling Cowboys are trying to determine how Neame picked up his throat injury in the Good Friday loss to the Dolphins.
Neame played the game out and made himself available to media post-match but once he explained his symptoms to medical staff he was sent straight to hospital, where he remained for two nights.
Scans later revealed a fracture to Neame's cricoid, a ring of cartilage that encircles the trachea. The Cowboy was discharged from hospital on Sunday.
The injury is a setback for the New Zealander, who was looking forward to welcoming a host of family members to the club's away clash against the Warriors this weekend.
He joins Heilum Luki, James Tamou, Murray Taulagi and Gehamat Shibasaki in North Queensland's casualty ward but State of Origin back-rower Jeremiah Nanai returns from suspension.
