Moore hurt the ankle near the end of Wednesday's practice and has been forced to sit out the past two days.
"[Moore's ankle] hasn't responded the way we wanted," Bears coach Lovie Smith. "If he has a miracle healing or something in between now and then [Sunday], we may consider letting him go. But it's not looking good."
Since winning the starting nickel job in summer 2010, Moore has solidified himself as one of the unit's top playmakers, and is tied for the team lead with three interceptions.
"It's difficult [to lose your starting nickel]," Smith said. "We consider nickel one of our starting positions. D.J. Moore has made a lot of plays for us. It's similar to the third receiver on the offensive side. We consider him and starter, and we'll miss him."
Corey Graham will replace Moore at nickelback against the Chargers. Graham made 10 career starts at cornerback since he entered the league in 2007, but has been used almost exclusively on special teams the past few years. However, Graham filled in for Moore in the fourth quarter last week and intercepted Lions quarterback Matthew Stafford.
"It would be very exciting [to start on Sunday]," Graham said. "I've been looking forward to it for a long time. I hope I get an opportunity to go out there and play. I really want to go out there and play on defense. That's something I've wanted for a long time. I'm very excited about it and just hope I get the opportunity."
Said Smith: "Corey Graham has played a lot of football for us around here, started a lot of games and we should be OK."
Jeff Dickerson covers the Bears for ESPNChicago.com and ESPN 1000.