New Orleans, LA (SportsNetwork.com) - Drew Brees threw five touchdown passes and hit 10 different targets, as the New Orleans Saints shook off the rust to post a 35-17 victory over the Buffalo Bills at the Superdome.

Brees had 332 yards on 26-of-34 passing for the Saints (6-1), who were coming off their bye. They suffered their lone loss of the season in heartbreaking fashion a week earlier at New England on a last-second touchdown pass by Tom Brady.

Star tight end Jimmy Graham and rookie wide receiver Kenny Stills both had two touchdown receptions for New Orleans. Graham was questionable heading into Sunday after suffering a foot injury against the Patriots, who held him without a catch.

Buffalo quarterback Thad Lewis was under pressure from the get-go. He fumbled three times, losing two, and threw an interception while completing 22-of-39 passes for 234 yards with a touchdown to wideout Stevie Johnson.

Johnson and tight end Scott Chandler both had 72 yards on seven catches for Buffalo (3-5), which has lost three of its last four games.

Fred Jackson ran for a 1-yard touchdown 40 seconds into the fourth quarter, trimming the Bills' deficit to 28-17. The drive was extended twice by roughing the passer penalties on cornerback Corey White.

Brees then put the game away following cornerback Keenan Lewis' interception. On the run, Brees heaved the ball down the field toward the end zone, where Stills made the 42-yard grab in one-and-one coverage.

"I thought we did do a few things better in the second half, forcing them to become a little more one-dimensional," said Saints head coach Sean Payton. "We were able to score and put a little distance in the fourth quarter with our lead."

The start was inauspicious and painful for Thad Lewis, who fumbled on the game's first play from scrimmage.

"We came out and we turned the ball over. We can't have that happen," said Bills head coach Doug Marrone.

The practice squad-turned-starting quarterback faked the ball to Jackson on a read option, but not long after he followed the running back through a hole on the right side, linebacker David Hawthorne dislodged the ball by driving his helmet into Lewis' right rib cage. Linebacker Junior Galette made the recovery for New Orleans and his modest return placed the ball at the Buffalo 22-yard line.

Lewis stayed on the ground for a couple minutes before walking slowly off the field.

The Saints wound up going backward following the turnover and came away with no points when Garrett Hartley missed a 47-yard field goal wide left.

To the surprise of many, Lewis was back on the field at the outset of the next Buffalo drive, which ended with Dan Carpenter missing a 50-yard field goal wide right.

"There was no doubt in my mind that after the very first hit that I was going back in the game," Lewis said. "I never doubted that - I just took some time to catch my breath because I had the wind knocked out of me a little bit, but I was fine and I just told the (doctors) that I was going back out there."

On the next Bills possession, defensive end Cameron Jordan forced and recovered a fumble on a sack deep in Buffalo territory.

This time, the Saints capitalized on the turnover as Brees connected with a returning Lance Moore for a 15-yard touchdown. The wide receiver missed the previous three games with an injured hand.

New Orleans then looked to pad its lead after converting a 4th-and-2 from the Buffalo 37, but Hartley was wide left once more. His 38-yard try came in the opening moments of the second quarter.

Lewis threw three consecutive passes to Johnson to begin the ensuing Buffalo possession, advancing the ball to the New Orleans 43. Tashard Choice followed with a 20-yard run before Lewis found Johnson for a 13-yard touchdown.

The Saints' defense then forced a third Lewis fumble as Galette rushed around the right side unimpeded and drilled Lewis from behind. The Bills, however, were able to recover the ball, and, in what became an uncommon occurrence, Carpenter actually converted a 37-yarder to put Buffalo up 10-7 with 4:35 remaining in the second quarter.

Brees quickly countered with a 69-yard touchdown pass to Stills, then threw a 15-yard scoring strike to Graham inside the final minute of the first half to give the Saints a 21-10 lead.

"Those were important. Up until that point we had done a number of things poorly," Payton said about the back-to-back touchdown drives.

Graham added a 13-yard TD reception in the third quarter.

Game Notes

Marrone was the offensive coordinator for the Saints from 2006-08 ... Buffalo running back C.J. Spiller (ankle) was inactive ... This was the first meeting between the Saints and Bills in the Superdome since Dec. 27, 1998. The Saints were the home team in the 2005 matchup played at San Antonio's Alamodome due to Hurricane Katrina.