Balotelli suffered the original injury during his debut against Timisoara in August. The 20-year-old was forced to have an operation that kept him out for two months, although he was quickly sidelined again through suspension after collecting a red card at West Brom.
However, Balotelli has not been seen since scoring a hat-trick against Aston Villa on December 28 and now Mancini has revealed the controversial front-man has suffered a recurrence of his knee injury. City medical staff have advised Balotelli to rest for four weeks and then resume training, in the belief that will rectify the problem.
However, Mancini is not happy at the situation and he said: "It is bad news. I am worried because he can't play for another three or four weeks at an important moment for us.
"To have an operation done and then to have another problem two months later is strange.
"He may need surgery. We just don't know. He must rest, then he will have treatment and work. Hopefully then he will be OK."
The concern over Balotelli is possibly why Mancini is reluctant to sanction the sale of Emmanuel Adebayor, even though new arrival Edin Dzeko was unveiled on Tuesday.
It was expected Dzeko's £27million capture would allow Adebayor and Roque Santa Cruz to end their unhappy periods at Eastlands. However, at the moment, Mancini is only prepared to let Santa Cruz leave.
"For Roque it is possible," said Mancini. "He is a good guy and he deserves to play. But with Emmanuel I don't know. We must wait and see."
Balotelli's injury also means Mancini will not have to face complaints from the youngster about his lack of match action, which seemed inevitable once Dzeko's services had been secured from Wolfsburg.