The Chelsea midfielder had just returned to training after a hamstring injury, which kept him out of the final two Premier League matches of the season.
But a fresh injury, thought to have been picked up on Saturday, is now highly likely to keep him out of the showcase match in Baku against Arsenal.
It is a major blow to Maurizio Sarri, who is already contending without Ruben Loftus-Cheek, Callum Hudson-Odoi and Antonio Rudiger.
There is now almost no midfield cover, with Danny Drinkwater out of favour and youngster Ethan Ampadu only just returning from injury himself.
It leaves Sarri to consider youngster Conor Gallagher as he bids to end the season with silverware.
It means there is added pressure on Jorginho, Mateo Kovacic and Ross Barkley to remain fit with the trio now almost certain to start on Wednesday.
Sarri lost Loftus-Cheek during the friendly match against the New England Revolution and admits the England midfielder faces a lengthy spell out.
“I’m sure he will be able to return stronger,” said Sarri of the midfielder.
“I don’t know the timing because it’s very difficult to say now: four months to six months.
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