Wickham was forced off on a stretcher in Palace's dramatic 5-4 defeat at Swansea on Saturday. The 23-year-old left the Liberty Stadium on crutches with his right knee heavily strapped, and a subsequent scan has revealed he will be now out of action for a significant period.
"Connor Wickham's injury sustained at the match against Swansea City on Saturday has seen him undergo an MRI scan and it is confirmed he received an anterior cruciate ligament injury to his right knee," Palace said in a statement.
"He will now undergo surgery and his return to action will be confirmed once rehabilitation starts following surgery.
"Everyone at the club wishes Connor a speedy recovery and we look forward to seeing him back in action as soon as possible."
Wickham, who has scored three times for Alan Pardew's struggling side this season, was applauded off the pitch by both sets of supporters at the Liberty Stadium following a seven-minute stoppage.
The former Sunderland striker had netted in successive matches against Burnley and Manchester City before sustaining the injury at Swansea.
Palace are just one point above the Premier League relegation zone following six consecutive defeats.