Manuel, Buffalo's first-round draft pick out of Florida State, was sacked seven times and doubled his interception total for the season.
The Bills have lost five of six, are assured of finishing without a winning record for the ninth straight year, and also are likely to extend the NFL's longest current playoff drought to 14 consecutive seasons.
Glennon wasn't exactly sensation following a 27-6 loss at Carolina, go 9 of 25 for 90 yards. But he had TD throws of 5 yards to Tim Wright and 38 to Vincent Jackson, who had three receptions for 70 yards to go over 1,000 for the season for the second straight year. Rainey finished with 127 yards on 22 carries.
Buffalo took up where it left off in a 34-31 overtime loss to Atlanta. The Bills lost fumbles on their final two possessions of that game, Stevie Johnson in the final minute of the fourth quarter and Scott Chandler two plays into OT.
This Sunday, they turned it over three times within a four-possession span of the second quarter, a stretch that might have been game-changing if Glennon hadn't thrown two interceptions.
After outgaining the Bills 169 yards to 38 while building a 14-3 lead, the Bucs were limited to 40 net yards over the next two quarters. The Bucs were held to a season-low 206 yards.
It didn't matter.
With Manuel throwing two more interceptions in the third period, the Bills never made a serious move to get back in the game, finishing with field goals of 40 and 46 yards by Dan Carpenter. Manuel hit C.J. Spiller on an 83-yard scoring play that was wiped out by a fourth-quarter holding penalty.
Manuel was picked off twice in the second quarter. Leodis McKelvin muffed a fair catch on a punt inside the Buffalo 20, and a roughing-the-passer penalty albeit a borderline call against Jairus Byrd helped set up Glennon's TD pass to Wright that extended Tampa Bay's lead to 24-3 at the half.
Byrd also had the 22nd interception of his career, moving him into a tie for 10th on Buffalo's all-time list. Stephon Gilmore's pick six minutes later prevented Tampa Bay from turning McKelvin's muff into points.
Linebacker Lavonte David had two of Tampa Bay's four interceptions. He also had a sack.