Newcastle lost for the first time in their Champions League campaign, falling to a 1-0 against Borussia Dortmund at St James' Park.
At the defeat may have wider consequences on the Magpies season, with Isak and Jacob Murphy having both picked up injuries in the game.
Isak, who has scored eight times this season already, was brought into the starting 11 in place of Callum Wilson but lasted just 15 minutes of the encounter.
Meanwhile, Murphy came off the bench in the 65th minute but had to be helped off the field five minutes later with his shirt being used as a makeshift sling.
Manager Eddie Howe told TNT Sports after the game: "Jacob came off with what looks like a serious injury.
"We've got a small squad as is it. That's probably the most disappointing thing of the night.
"It looks like a recurrence of his Isak's groin problem and it's a big blow. Jacob's looks serious, potentially a dislocation of his shoulder."
And according to Mail Sport's Craig Hope, Isak is set to miss a crucial run of games for Newcastle.
Hope said on X, the social media platform formally known as Twitter: "Understand Alexander Isak unlikely to return before next international break after suffering recurrence of groin injury v Dortmund.
"That could rule him out of 5 matches. Problem not thought to be too serious, but still a blow to be down to one striker for some huge games."
Should Isak miss the next five games, he would be absent for Newcastle's Premier League contests against Wolves, Arsenal and Bournemouth, as well as a Carabao Cup encounter at Manchester United and Champions League visit to Borussia Dortmund.
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