The 28-year-old complained of pain in his left knee during the Rosanero's 2-2 draw with AC Milan, and medical examinations have subsequently confirmed the extent of his injury.
A statement issued on palermocalcio.it today read: "During the first half of our game against Milan, Andrea Mantovani reported a problem with his left anterior cruciate ligament.
"The injury was confirmed by medical tests conducted on the Rosanero defender.
"(He) will undergo surgery in the coming days at Villa Stuart."
Palermo head coach Gian Piero Gasperini is already without the services of striker Abel Hernandez, who suffered the same injury last month.