Ayew, 23, was substituted after feeling pain in his left knee during the second leg of Ghana's 2014 FIFA World Cup play-off against Egypt on Tuesday.
Ghana comfortably won the tie 7-3 on aggregate triumph, but the news is bad for Ayew who has been diagnosed with a meniscal tear in his knee.
The forward will go into surgery on Monday and is tipped to miss up to eight weeks, according to a club statement.
"Ayew went through diverse examinations on his return to Marseille on Wednesday afternoon by Marseille's medical team, led by Christophe Baudot," it read.
"He went through more examinations this Thursday morning have confirmed the initial diagnosis: Andre Ayew has a non-stable external meniscal tear.
"This requires surgery, and will be led by Dr Jean-Pierre Franceschi, in Marseille."
Ayew has made 14 appearances in all competitions this season, scoring four goals.
