Isak played only in the first Nations League match, scoring in the win over Romania, before the Football Association announced that he would miss the other three matches with a minor injury.
Isak, who has struggled with injuries in recent seasons, has scored four goals in five Premier League games this season.
In addition to Isak, Liverpool will also be without striker Cody Gakpo against Man City. Gakpo is also dealing with an injury.
"Alexander Isak and Gakpo will not play. Unfortunately, they are not ready. They were injured during the international break," Liverpool coach Andoni Iraola said, according to the Liverpool Echo.
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