Sergio Aguero has been ruled out for a month and David Silva could be sidelined for three weeks as Manchester City are set to face a pivotal spell in their season without their top two scorers from last term.
Striker Aguero, who scored five times in 20 minutes against Newcastle last week and won the Premier League's Golden Boot following his 26 goals last campaign, was hurt in Argentina's defeat to Ecuador.
And the 27-year-old told TyC Sports in Buenos Aires: "I think I'll be a month without playing."
Midfielder Silva, who struck 12 times last season, came off in Spain's 4-0 win over Luxembourg with a sprained ankle that could reportedly keep him out for three weeks. He was withdrawn from the Spain squad for Monday's trip to Ukraine.
Both are set to miss the Manchester derby on Oct. 25 and the Champions League home game against Sevilla four days earlier, while Aguero is also unlikely to play in the return fixture in Spain.
The former Atletico Madrid player is also set to sit out Premier League games against Bournemouth, Norwich and Aston Villa and the Capital One Cup tie with in-form Crystal Palace.
In Aguero's absence, City's only specialist senior striker is Wilfried Bony, who has scored just two goals in 19 games for the club.
Manager Manuel Pellegrini can also call upon teenager Kelechi Iheanacho, who has scored one first-team goal, and has said he is willing to use winger Raheem Sterling as a striker.
However, with Silva injured and with Samir Nasri missing City's last two games with a hamstring problem, the £49 million man could be needed in midfield.
Pellegrini said before the 6-1 win over Newcastle that he hoped City's injury problems were coming to an end after he was without an entire team for the 4-1 Capital One Cup victory over Sunderland.
"It is not normal what we had in the last weeks," he said in a news conference. "Against Sunderland we have 11 players injured. After that we have an average of seven, so I think it is too much and I hope in this international break most of them will be fit."
City are waiting to see if captain Vincent Kompany recovers from his calf injury, while Gael Clichy is yet to play this season after ankle surgery. Fabian Delph, who has spent two spells on the sidelines with hamstring problems, will also have his fitness monitored.