The Patriots (8-5) built a 17-0 lead in the first 12 minutes and never looked back to move into sole possession of first place in the AFC East, a half game ahead of the Miami Dolphins, who play Chicago on Monday night.
Buffalo (6-7), which turned the ball over five times, has lost four of its last five games and trails the Patriots by two with three to play.
"We had a good game plan coming in and I think we did a lot of things," Bledsoe said. "We just made a lot of mistakes that killed us."
The top overall pick by the Patriots in 1993, Bledsoe spent his first nine seasons in New England. But things there ended on a sour note for Bledsoe, who suffered internal injuries in Week 2 last season against the New York Jets.
That game was Bledsoe's last appearance in Foxboro until Sunday and he hoped to make amends for his lackluster performance in a 38-7 loss to the Patriots in Buffalo on Nov. 3.
Bledsoe, who received a warm ovation before the game, passed for 328 yards, but was ineffective early when the Patriots fell into a deep hole. He completed 32 of 51 passes, but threw four interceptions in a game for the first time since 1999 and was one shy of a career high.
"It was nice to be appreciated back here, but certainly not the way I envisioned it," Bledsoe said. "I wanted to walk off the field victorious."
"A few of those throws obviously you'd like to have back," Buffalo Coach Gregg Williams said. "He's a competitor and he normally can make tight throws. He put a couple of them in there in situations where he couldn't get it in there."
"I don't think it matters if Drew is coming back. It doesn't matter," Brady said. "I'm always trying to be efficient. I'm always trying to make the right reads and throws."
Brady, who took over for Bledsoe last season and led the Patriots to a Super Bowl title, connected on a 41-yard pass to rookie Deion Branch on the first play from scrimmage. That led to a 39-yard field goal by Adam Vinatieri.
New England marched 86 yards in eight plays on its next possession. Brady completed a 33-yard pass to tight end Christian Fauria and receiver Troy Brown had a 21-yard run before Brady connected on a 10-yard scoring strike to David Patten.
Brady completed 15 of 27 passes for 183 yards and was not intercepted.
Bledsoe was intercepted by tackle Richard Seymour on his next attempt, giving the Patriots a first down at the Buffalo nine. Two plays later, Brady completed a nine-yard touchdown pass to Donald Hayes.
The Patriots increased their halftime lead to 20-0 on a 46-yard field goal by Vinatieri late in the second quarter.
Buffalo cut the lead in half in the third quarter as Mike Hollis kicked a 26-yard field goal and Bledsoe threw a 12-yard touchdown pass to Eric Moulds. Former Bill Antowain Smith increased the lead to 27-10 with a four-yard run early in the final quarter.
Moulds caught his second touchdown pass of the game with 65 seconds left, grabbing a four-yarder from Bledsoe.
New England has taken the last five meetings between the teams.