Safety and captain Donte Whitner has a separated right shoulder and could miss significant time.
Bills coach Dick Jauron on Monday afternoon called the injury "fairly significant" and said Whitner would be assessed on a week-by-week basis.
"It's not the best news we got," Jauron said.
Jauron sounded grim in projecting Whitner's availability for Sunday's game against the New England Patriots in Gillette Stadium.
"We won't rule anybody out until we have to. But we're talking week-to-week and this is the first week."
Whitner came off the field with about 6:50 left in the game. He was unavailable to comment Monday.
Many consider Whitner the man who makes the Bills defense work. Although tackles are an unofficial stat, statspass.com has Whitner third in tackles among NFL defensive backs since he entered the league in 2006. The Bills list him with 232 career tackles, behind only Gibril Wilson and Lawyer Milloy.
"It's a tough loss," Bills quarterback Trent Edwards said. "Donte is a leader in this locker room, a leader on Sunday out there on the field.
"The thing about this team is we faced a lot of injuries last year. We had guys step up at those big-time positions for us. Guys who haven't played all that much because Donte's been in there need to step up and take over that role."
Making matters worse for Buffalo's defense, it sounds like Pro Bowl end Aaron Schobel has experienced a setback.
Jauron initially said Schobel remains day-to-day with a foot injury, but added "maybe he should be week-to-week now, too."
The Bills are 1-2 in the games Schobel has missed and didn't register a sack Sunday.