Brady completed 23 of 27 passes for 310 yards with two of the touchdown throws going to running back Antowain Smith.
The Patriots-Bills meeting was billed as a revenge game for Buffalo quarterback Drew Bledsoe, who lost his starting job to Brady at New England last season after suffering an injury early in the campaign.
Brady went on to carry the Patriots to a Super Bowl title, after which Bledsoe was traded to Buffalo for a first-round pick in 2003.
However, with Bledsoe throwing for 2,500 yards in the first eight games of the season and Brady struggling through a four-game losing streak with New England (4-4), a debate had begun about whether the Patriots might have traded the wrong quarterback.
"We just needed a win to get back on the right track," Brady said. "It really had nothing to do with 'Brady and Bledsoe' especially since Drew was very well liked and respected and did a lot for this organization."
Brady victimized the Bills (5-4) with screens and hit eight different receivers. He completed his first 10 passes on New England's first two scoring drives, connecting with tight end Christian Fauria on a five-yard touchdown 4:33 into the game and with Smith on a 13-yard score with 12:54 left in the half.
He completed his first 10 passes for 104 yards, including touchdowns of five yards to tight end Christian Fauria and 13 yards to Smith in the first half.
During the second half, Brady completed 13 of 14 for 201 yards and two touchdowns.
"It's important to fight back when it's not really going your way and we had a lot of fight today," said Brady, who threw for a season-low 130 yards last week in a loss to Denver.
Running back Kevin Faulk turned a screen pass into a 45-yard scoring play with 7:33 left in the third quarter to increase New England's lead to 24-7.
Brady and Smith virtually sealed the win later in the quarter. Facing fourth and three at the Buffalo 34, Belichick elected to go for the first down and Brady hit Smith with a four-yard pass.
Brady followed with passes of 19 and nine yards to David Patten to the Buffalo two. Three plays later, Smith went off left tackle for a two-yard touchdown with 54 seconds left in the third quarter.
"I know everybody wants to hype the Bledsoe story, but the important part is that we beat Buffalo, a division team, on the road," Belichick said. If you want to do well in your division you have to do well against the division teams. I'm really proud of the way our ballteam played today. It was a good team effort. I thought that offensively, defensively, special teams, each one complemented the other one."
Bledsoe threw for 302 yards, his fifth 300-yard game of the season, but engineered just one scoring drive, hitting Peerless Price with a one-yard touchdown pass with 10 seconds left in the half. The Patriots sacked Bledsoe four times.
"I know those guys very well, obviously, and if there is a defining characteristic of the Patriot team I was a part of, is they have a lot of guys with high characters," said Bledsoe, who completed 28 of 45 passes. "We knew they'd come in with a sense of desperation. They came out and played very, very well."
While many were looking for Bledsoe to haunt his former team, it was Smith who did the trick. Waived by the Bills after the 2000 season, Smith rushed for a season-high 111 yards and a touchdown on 29 carries and caught five passes for 31 yards, including scores of 13 and 14 yards.
"A lot of that (playing against Buffalo) has died down," said Smith, who had 195 yards rushing and two touchdowns in two wins over Buffalo last season. "My main thing is I want to go out there and make plays and help my team win."
Meanwhile, Travis Henry had just 11 carries and produced 53 yards for the Bills, who abandoned the running game after falling behind by 17 points in the third quarter.
However, the Patriots rank second in the NFL in pass defense and cornerback Ty Law, who shadowed Eric Moulds most of the day, had an interception. Price led the Bills with nine receptions for 98 yards and Moulds had five catches for 68 yards.
"Really what they did was play a similar style of defense to what they played last year when they went on the (championship) run," Bledsoe said. "They gave us some yards here and there but ultimately tightened up when we got into scoring territory."
Buffalo's Mike Hollis missed three field goals, including a 25-yarder in the second quarter.
The loss snapped a three-game winning streak for the Bills, who failed to move closer to first-place Miami (5-2), which plays at Green Bay on Monday, in the AFC East.
"It comes down to tackling and we missed numerous tackles in the open field on those screen passes," Bills Coach Gregg Williams said. "They out-executed us today, they came in with a good solid game plan and played well. The better team today on the field won the game. We did not play well enough."
When New England lit up the scoreboard for 115 points in its 3-0 start, Brady threw for nine touchdowns and two interceptions. In the four-game skid, he had six touchdowns and seven interceptions.
But Brady had the Bills defense off-balance throughout the day. On New England's first scoring drive, he hit six different receivers for 61 yards, including the touchdown to Fauria in the back of the end zone 4:33 into the game.
"That pretty much set the tempo for us," Brady said. "That first drive was a confidence builder."