Manuel has a left knee sprain that kept him out of last week's game against Miami, in which Lewis completed 15-of-25 passes for 193 yards and one interception, as the Bills beat the Dolphins 19-0 and improved to 6-9.
Manuel is technically listed as "doubtful" for Sunday's game against the New England Patriots.
"It was a tough decision," Marrone said Friday. "EJ was practicing hard all week trying to come back and basically it goes back to the injury didn't progress as well as I wanted it to.
"He wanted to go out there and play but I need him to play at 110 percent for us to win. So he wasn't going to be able to go out there and play at 110 percent. He could have played but not at the level that we need for us to win.
"Thad has done a nice job and he's the backup quarterback, so we're putting him in there and he'll be the starter Sunday."
Manuel, a rookie, missed six games this season with a right knee sprain. He completed 180-of-306 passes for 1,972 yards with 11 touchdowns and nine interceptions.
Lewis, in his third NFL season, is 77-of-128 passing for 845 yards and three touchdowns against three interceptions in five games this season. He played for the Cleveland Browns for two years, appearing in one game, before joining Buffalo.