Chandler was hurt on the Bills' third play from scrimmage after he fell awkwardly while making a 25-yard catch. He was walking on crutches following the game, and coach Chan Gailey said the injury "doesn't look good."
A league source told ESPN's Adam Schefter that Chandler has a torn anterior cruciate ligament.
The Bills close their season against the New York Jets on Sunday.
Chandler and Stevie Johnson are tied for the team lead with six touchdowns receiving. Chandler has 43 catches for 571 yards.
Information from The Associated Press was used in this report.