The Argentina international has been sidelined since sustaining knee ligament damage in the La Liga match against Las Palmas on September 26.
There were hopes Messi would be fit for the November 21 clash against fierce rivals Real at Santiago Bernabeu - but Argentina's team doctor, Homero de Agostino, says there's a chance Messi could face an even longer spell out if he plays.
"The risk of aggravating the injury if Messi plays the Clasico is high," he told Cadena SER.
De Agostino said he doubted whether the 28-year-old would be back to fitness in time for the top-of-the-table clash.
"I don't think that he can get in condition to play the Clasico," he said.
"The coach [Luis Enrique] cannot rely on a newly recovered player."
Messi has been left out of the Argentina squad for upcoming World Cup qualifiers against Brazil and Colombia.