During the first half of the 3-0 victory against AC Milan, Fofana opened his account for the Blues by giving his team the lead, coolly slotting into the far corner from close range after a goalmouth scramble.
However, before the end of the opening period, the France international appeared to jar his knee in a tussle with Fode Ballo-Toure.
The £70m summer arrival attempted to continue after treatment on the pitch and sidelines before eventually having to hobble off to be replaced by Trevoh Chalobah.
After the game, head coach Graham Potter acknowledged that he had been left "concerned" by the injury, one which required the 21-year-old to depart Stamford Bridge on crutches.
According to L'Equipe, Fofana will now be sidelined for around four weeks with scans revealing a sprain to his knee.
While that prognosis felt like a best-case scenario when Fofana went down on Wednesday, Potter will still be disappointed by the player's absence over the next month.
Chelsea have 11 fixtures in all competitions scheduled for before the World Cup, that run concluding with a trip to Newcastle United on November 12.
Seven of those matches will take place in the Premier League, while three of the remaining four are crucial games in Group E of the Champions League.
Fofana may be in a position where he can make at least one appearance before the World Cup in a bid to stake his claim for a spot in the France squad.
However, from Potter's perspective, he must find a way to manage the fitness of his other central defenders with Thiago Silva, Kalidou Koulibaly and Chalobah the only other three traditional players for that position in the squad.
The Englishman could instead have to call upon the likes of Reece James, Cesar Azpilicueta and Marc Cucurella to deputise, particularly in a back three.
At some point, however, Potter may wish to pick and choose the game time for 38-year-old Thiago Silva, who has already made nine starts in all competitions this season.