Mitchell Pearce should be back before the end of the NRL season, but he won't be playing State of Origin in 2018.
Pearce will spend up to four months on the sidelines after scans confirmed he has a ruptured pectoral muscle.
The playmaker left the field late in Newcastle's win over the Wests Tigers on Saturday night and he requires surgery on the muscle.
The injury will rule him out for 16 weeks, meaning he will miss the entire State of Origin series for NSW and the majority of the Knights' season.
The injury will place a large stress on the Knights who are already waiting on five-eighth Connor Watson to return from a shoulder injury, with youngsters Jack Cogger and Brock Lamb as coach Nathan Brown's other options.
But their pain will be equalled by that of Blues coach Brad Fittler, who has now lost his incumbent while potential replacement Nathan Cleary is still sidelined with a knee injury for another month.
The probable unavailability of both Pearce and Cleary for the June 6 series-opener significantly whittles down the list of possible options to partner likely five-eighth James Maloney.
Luke Keary has been in strong form for the Sydney Roosters, while Wests Tigers No.7 Luke Brooks has also recently been tossed up as a possibility to make his Origin debut.
Other candidates include South Sydney playmaker Adam Reynolds, Cronulla link-man Matt Moylan and Brisbane five-eighth Jack Bird, each of whom have previously pulled on the Blues jumper.
"It's not great," Knights coach Brown said of Pearce after their 22-20 win over Wests Tigers.
"He is disappointed. Mitch loves playing. Game day is his favourite day of the week.
"They are the types of players you want in your club. Whatever the result is he will still contribute while he is not playing."