Manuel, the first quarterback chosen in April's draft, underwent a minor procedure on his left knee Aug. 18 and missed the team's final two preseason games.
Manuel is back to full speed, coach Doug Marrone says.
"He's 110 percent healthy," Marrone said. "He looks good out there. So that's what we're going to go with."
The 16th overall pick was a combined 26-of-33 passing for 199 yards and two touchdowns without an interception in his two preseason appearances.
Marrone said last week that the Bills had planned on starting undrafted rookie Jeff Tuel, the only other quarterback on Buffalo's active roster, if Manuel was unable to play. But Manuel returned to practice Sunday, wearing a brace on his left knee.
Marrone said Manuel's recovery from the procedure was progressing ahead of schedule, and Manuel practiced fully on Monday. Marrone said the original plan was to have Manuel return to practice on a limited basis Monday.
"When he first came back, I was like 'Wow, he looks pretty good,'" Marrone said. "Then the thing was to be smart about it. When it started to move up, I started to feel like this was the way we were going."
At this point, Marrone said, the Bills aren't concerned with Manuel re-injuring his knee.
"What I was trying to make sure of was, by putting him back there, was there any chance [for it] to get worse?" Marrone said. "Once that was taken out of the equation, I felt very comfortable with the situation.
"Being Catholic, there was a lot of prayers," Marrone joked. "Honestly, you go home and say, 'I hope he's healthy, I hope he's healthy.' But you really don't know."
Although Sunday will mark Manuel's first NFL start, Marrone said he won't be lowering his expectations for the rookie.
"I'd be lying if I'm standing here saying that I don't expect him to do great things," Marrone said. "That's why he's out here. We expect not just EJ, but all of our players that are out there, to perform at a high level. If I lower my expectations of anybody on this team, am I doing my job as a coach?"