The starting duo will miss the remainder of the 2017-18 season as the Eagles attempt to fight the drop.
Crystal Palace manager Roy Hodgson has confirmed that Scott Dann and Jason Puncheon could undergo surgery after damaging their cruciate ligaments in a 0-0 draw with Manchester City.
However, the Eagles pair won't return to the squad until next season, something that could force Hodgson's hand in the January transfer market.
Dann, who has captained the side in Puncheon's absence this season, has already made 17 Premier League appearances this season - more than any other center back at the club.
Puncheon, however, has been in and out of the squad for much of the season. A regular part of Frank de Boer's squad at the start of the season, the former Southampton midfielder has made just appeared just six times - out of a possible 18 appearances - since the Dutchman's sacking.
"Dann and Puncheon are both cruciate ligament injuries," the club confirmed on their Twitter page. "They'll both see a specialist and likely undergo surgery once the swelling goes. We won't see them play again this season and may not be ready for the start of next. They're very serious injuries."
Palace will be desperate to bolster their squad in the January transfer window to avoid relegation this season. The Eagles also have to make sure they can fend off any interest in their star players, especially given Arsenal's interest in Wilfried Zaha.
Crystal Palace now have their first brief rest since the busy Christmas schedule began, with an FA Cup match against Brighton set for January 8. The Eagles then return to Premier League action by hosting Burnley, with London derbies against Arsenal and West Ham still to come this month.