But not before Manning nearly pulled off another fourth-quarter comeback in a career filled with them.
In their 13th meeting, and first since Manning left the Indianapolis Colts, Brady directed four scoring marches of at least 80 yards and the Patriots won 31-21 on Sunday. He's 9-4 in his career against Manning.
"Nobody I'd rather have than Tom Brady," New England coach Bill Belichick said, "but Manning's a great player."
Manning had led his teams back in the fourth quarter to 36 comeback wins. And the Broncos (2-3) rallied from a 31-7 deficit with about five minutes left in the third quarter on Manning's scoring passes of 2 yards to Eric Decker and 5 yards to Brandon Stokley.
The Patriots (3-2) lost the ball on Stevan Ridley's fumble on their next possession and Manning completed a 28-yard pass to Demaryius Thomas to the Patriots 14-yard line. But two plays later, Denver's comeback hopes faded when Willis McGahee fumbled and Jermaine Cunningham recovered at the New England 11 with 3:42 remaining.
"We can build on that" ability to whittle a big deficit, Manning said. "I do think that will help us win a game at some point."
Brady downplayed his meeting with Manning.
"It's Patriots-Broncos," he said. "It was a great team win. We got some turnovers from our defence and I thought offensively capitalized at times. There were a few lulls in there, which I wish we had executed a little bit better, but for the most part it's a good day."
Brady completed 23 of 31 passes for 223 yards and one touchdown and ran for another, operating much of the game out of a no-huddle offence.
"It's not new," Denver coach John Fox said. "They've been doing this for a long, long time. They just have a good group of guys together doing it. ... Our guy (Manning) did an outstanding job today as well."
Manning was 31 of 44 for 345 yards and three touchdowns but lost a fumble on a third-quarter sack.
That led to Ridley's 8-yard run that put the Patriots ahead 31-7. Ridley led the Patriots with a career-high 151 yards rushing. They gained 251 yards on the ground, one week after rushing for 247 in a 52-28 win over the Buffalo Bills.
"It's awesome," Ridley said. "It takes a lot of pressure off Brady. And that's our leader."
The Patriots set a franchise record with 35 first downs as they kept their offence rolling one week after gaining 580 against the Bills. The Broncos sputtered after beating the Oakland Raiders 37-6. Their previous two losses were by just six points to the Atlanta Falcons and Houston Texans.
"I know they're been great teams we've lost to, which still doesn't make it any easier," Manning said. "We are working on things and building things. It doesn't happen right away."
Brady and Manning first faced each other in the third game of the 2001 season. The Patriots won 44-13 in Brady's first career start.
There were plenty of close games in subsequent regular-season matchups with six of the previous seven decided by seven points or less.
But, Manning said, "this is not a team you want to fall behind to."
The Patriots led 17-7 at halftime and 31-7 after three quarters. Brady and his runners kept slicing through the Denver defence with a balanced attack. They went ahead to stay, 14-7, midway through the second quarter on a 14-play drive (seven pass plays and seven runs) capped by Shane Vereen's 1-yard run.
Ridley had his third 100-yard rushing game of his career, all this season. Wes Welker, the NFL's leading receiver last year with 122 catches, had 13 for 104 yards.
"There were a few times where I didn't get open," he said, "but for the most part I feel like I got open a lot and was able to make some plays."
The Broncos wasted an excellent opportunity on their first series. Manning hit Thomas with a 43-yard completion to the Patriots 10-yard line, but Sterling Moore stripped the ball and recovered the fumble. The Patriots went four-and-out on the ensuing possession then the Patriots scored on their next three possessions -- 84 yards to Brady's 8-yard pass to Welker, 80 yards to Vereen's touchdown and 93 yards to Stephen Gostkowski's 23-yard field goal.
Denver did tie the game 7-7 on Manning's 1-yard pass to Joel Dreessen but didn't reach the end zone again until Manning hit Decker to end a 90-yard march, cutting the lead to 31-14 with 1:08 left in the third.
But Manning couldn't bring the Broncos all the way back.
"A week ago, we put it all together," Fox said. "I would have expected us to put it all together more this week."
But Brady and his offence is a lot tougher than the Raiders.
"You have to be balanced and I think we were doing a very good job when we're calling the runs," Brady said.
Notes: McGahee rushed for just 51 yards on 14 carries after gaining more than 100 in two of his previous three games. ... The Patriots rushed for more than 200 yards in consecutive games for the first time since 1978. ... New England outgained Denver 444 yards to 402.