Doucoure left the field on a stretcher after he went down unchallenged in the second half at Kenilworth Road.
Palace could be without Doucoure for six months in a major blow to the Eagles.
The 23-year-old Mali international will also miss the Africa Cup of Nations next year.
Speaking after the Luton defeat, Palace manager Roy Hodgson said: “He’s got a bad injury. I’ll let the doctor deal with that first. It’s not going to be an injury that keeps him out for a short period of time.”
Doucoure joined Palace for an initial £18million from Lens last year and shone last season, his form attracting interest from Liverpool.
Meanwhile, Eberechi Eze was also substituted with an injury on Saturday and will be assessed this week to determine whether he can face West Ham on Sunday.
Eze had only just returned from a month-long hamstring injury.