Khedira was forced off in the 20th minute of Wednesday's 2-1 Champions League defeat at Borussia Dortmund when he aggravated a leg muscle problem and his replacement, Luka Modric, is not as accomplished in the central holding role alongside Xabi Alonso.
Another option for coach Jose Mourinho is Modric's fellow new signing Michael Essien, but with Marcelo, Fabio Coentrao and Alvaro Arbeloa also sidelined, the former Chelsea midfielder has been filling in at left-back.
Essien looked uncomfortable against pacy Dortmund pair Lukasz Piszczek and Marco Reus on Wednesday and goalkeeper Iker Casillas acknowledged the left side of defence was a problem.
"It's true that they got a lot of joy down our left wing," the Real and Spain captain told reporters.
"You noticed it a lot in the game," he added. "We are suffering a lot of injuries and Khedira's is another setback."
Real have clawed their way up to fourth after a poor start to the defence of their title but remain eight points behind joint leaders Barcelona and Atletico Madrid and three behind third-placed Malaga.
Barca play at Rayo Vallecano and Malaga are away to Espanyol on Saturday, while Atletico host Osasuna on Sunday.
SELECTION HEADACHES
Mallorca, coached by the wily and experienced Joaquin Caparros, have made a solid start to their campaign and the Balearic islanders are eighth on 11 points.
New signing Giovanni dos Santos made his debut against Sevilla on Monday and provided two goal assists as Mallorca fell 3-2 at the Sanchez Pizjuan despite twice taking the lead.
The 23-year-old Mexico forward, a graduate of the Barcelona youth academy, signed for Tottenham Hotspur in 2008 but failed to settle and had loan spells with Ipswich Town, Galatasaray and Racing Santander.
After helping Mexico win gold at the Olympic Games in London this summer, he sealed a move to Mallorca, where he hopes to find some of the consistency that has so far eluded him.
"It's clear that I will get a lot better as long as I keep getting more time on the pitch, I know that," Dos Santos said in an interview with As sports daily published on Thursday.
"I know that I still need to improve," he added.
Barca have their own selection headaches for the Rayo game, especially in defence with centre-backs Carles Puyol and Gerard Pique and right-back Daniel Alves all injured.
They will also almost certainly be without Javier Mascherano after he was sent off in Saturday's 5-4 win at Deportivo La Coruna.
Barca said on Wednesday they had lodged an appeal against the dismissal, although the football federation (RFEF) is unlikely to exonerate the Argentine, a converted midfielder who plays in central defence.
