The Euro 2012 finalists will miss both the Juventus midfielder and Andrea Barzagli as they take on the Copa America holders on Sunday
The defender is being plagued by a tendon problem that recurred in the Confederations Cup semi-final defeat against Spain on Thursday and was replaced at half-time due to his physical problems.
Pirlo, on the other hand, lasted for the full 120 minutes against Spain, but muscular problems now see him miss the game versus Uruguay.
"Pirlo was coming off a muscular problem and did brilliantly to resist throughout the entire match with Spain," team doctor Enrico Castellacci was quoted as saying on the official FIGC website. "However, as a precautionary measure and in agreement with the coach, we have decided not to risk him for the next game.
"Barzagli is suffering from a recurring tendon problem that had already affected him recently."
Italy will also be without star striker Mario Balotelli in the third place playoff as the AC Milan attacker was sent home earlier this week due to injury.