Fofana has undergone surgery and will miss a significant portion of the 2023/2024 campaign.
The 22-year-old has not travelled on Chelsea's pre-season tour of the United States.
Fofana joined Chelsea for £70m from Leicester City last season and made 20 appearances across all competitions, scoring two goals.
The Frenchman missed more than two months of action last season following a knee injury suffered against AC Milan in the Champions League in October.
Fofana also suffered a broken leg in August 2021 while at Leicester City and missed seven months of action.
A club statement from Chelsea on Tuesday read: "Defender Wesley Fofana has undergone anterior cruciate ligament reconstruction surgery.
"The 22-year-old did not travel to America for the club's pre-season tour due to specialist medical assessments, which unfortunately confirmed that an operation would be required.
"Wesley will now begin his recovery and work with the club's medical department at Cobham during his rehabilitation phase."
Fofana's injury is an unwelcome piece of news to new Chelsea manager Mauricio Pochettino, who could be forced to dip into the transfer market for a new defender, with Kalidou Koulibaly and Cesar Azpilicueta having already left the club.
