The Spain internationals picked up injuries in the friendly against Italy and could be sidelines for a number of days, meaning they could miss out against their La Liga rivals
The duo sustained injuries in Spain's 2-1 international friendly loss against Italy on Wednesday and could be ruled out of action for Sunday's encounter at Santiago Bernabeu.
Pique picked up a knock in the dying minutes of the first half and was forced to leave the pitch due to the knock. Busquets, who replaced Pique, managed to stay on the pitch until the final whistle, but complained about a knee problem after the game.
However, Spain's physio, Juan Cota, said to Sport that both players could feature if their injuries suffer no further ill-effects.
"Busquets was on the receiving end of a tackle and has a painful knee. Fortunately, it doesn't seem to be too serious. Pique has a muscular problem. He could be recovered in time for Sunday if nothing happens in the next few days."
The first leg of the Spanish Supercopa tie takes place at Santiago Bernabeu this weekend, while the return will be held at Camp Nou three days later.