Kevin de Bruyne will miss up to six weeks with a hamstring injury.
This was confirmed in a news conference by manager Pep Guardiola.
The 29-year-old sustained the injury on Wednesday against Aston Villa in a 2-0 win.
Manchester City are second in the Premier League table 2 points behind Manchester United with a game in hand and his absence will begin with the FA Cup fourth-round match on Saturday against Cheltenham.
They are unbeaten in their last 16 matches in all competitions and have won their last nine.
De Bruyne could miss up to 10 matches, including the Champions League last-16 first-leg tie with Borussia Monchengladbach on 24 February.
“The doctor said after reviewing the scan Kevin will be out for four to six weeks. It’s a big blow, but we have to move forward,” said Guardiola.
“I’m not saying anything that anyone doesn’t know – it is unfortunate for him and for us and we have to find a solution because everyone in their own life is struggling in the situation we are living in and we have to adapt.”
As well as the FA Cup tie at League One Cheltenham Town, De Bruyne will also miss Premier League matches against West Brom, Sheffield United and Burnley as well as games against fellow title contenders Liverpool on 7 February at Anfield and Tottenham at home six days later.
He could also be absent for the home league game against Arsenal, the Champions League tie against Monchengladbach and the Premier League encounter with West Ham. City are then scheduled to play a derby game against Manchester United on 6 March.