"We were not able to get that swelling to respond to the treatments the way we wanted," coach Doug Marrone said. "He was able to throw the ball in the pocket, but the stability in that knee, with the swelling, he does not have the escapability or the ability to run after the fake or zone read or those type of things that we feel is important to us to win."
Thad Lewis, who started three games when Manuel was sidelined with a separate knee injury earlier this season, will start again for Manuel on Sunday. Lewis has a 1-2 record as the starter, defeating the Dolphins in the teams' first meeting Oct. 20.
The Bills also will be without wide receiver Stevie Johnson, who has been excused to be with his family in California after the death of his mother.
Marrone said he is "110 percent confident" that Manuel will play in the Bills' season finale at New England and that the team will not consider "shutting down" its rookie quarterback.
"Every snap, every time we can get him in there, that type of experience, the better and better he gets," Marrone said. "I don't even think of [shutting him down]."
This is the third time Manuel has injured a knee this season. He had a minor procedure during the preseason to reduce swelling in his left knee and missed four games after spraining his right knee in a Week 5 loss to the Cleveland Browns.
Marrone addressed the possibility that Manuel, the 16th overall pick in April's draft, will be labeled as "injury prone" and said he prepped Manuel on how to answer questions about his durability.
"People are going to think that and write that. I totally understand that. But my personal opinion is this: He's not injury prone," Marrone said. "His history has shown that he's never been hurt. He's gotten hurt here, yes. He re-injured that left knee that hurt in training camp. When he has been injured, he has done everything he has could to come back faster than what was expected, faster than what was possible."
Manuel has characterized his knee injuries this season as "freak accidents" and said he is not injury prone.
"I've been playing this game for 20 or however many years and I've never had recurring injuries, especially with me knees," Manuel said. "You obviously don't want to get the tag as 'injury prone' or 'soft' or things like that, and I know I'm not that. But you still have to be smart with your body and have a nice, long career."
Marrone has said that Manuel must be smarter about protecting himself as a runner.
"I feel that we've learned from that experience and he's gotten better with how he's played," Marrone said. "We've got to keep working that and making sure he makes the right decisions."
Manuel suffered his latest injury late in the first half of Sunday's win over the Jacksonville Jaguars.
"When it happened in the game, I just said to myself, 'Is this really happening again?' I just taped it up and kept playing," Manuel said. "It's like freak accidents, man. It's crazy."