Regarded as two of the finest the NFL has ever seen, either Manning or Brady has represented the AFC in seven of the last 11 Super Bowls.
Brady has had the better of the 12 encounters between the two, winning eight of them, but this is the first time that Manning heads to Foxborough with the Broncos, having left the Indianapolis Colts following his year out with injury.
Manning's Broncos are 2-2 in the AFC West and Brady believes the NFL is better for the quarterback's return.
"The league certainly missed him when he wasn't in there last year. He's an incredible player and competitor," the Patriots quarterback said.
"We've had our fair share of meaningful games against a Peyton Manning-led offense when he was with the Colts. He seems like he's got this team really in the hunt as well.
"They lost two very close games and were in it right until the end. He's a phenomenal player, leader and quarterback and it's great watching him play out there," Brady said.
Patriots head coach Bill Belichick is not surprised to see Manning, who has put up 1,162 yards in four games and thrown eight touchdowns, looking a threat again after four operations on his neck.
"I think Peyton's one of the players that just really works hard all the time, works hard at everything," Belichick said.
"Lots of preparation every week and all the fundamentals: his footwork, throw mechanics, ball handling, all those things.
"I don't think there's really any weakness in his game. He works hard at all the little things and you can see it on film. They all show up."
New England lost in weeks two and three, with the Arizona Cardinals and Baltimore Ravens bettering them, but they bounced back with an impressive 52-28 win at Buffalo last week.
Manning says that his year off has meant extra work in preparing for the Patriots' defense.
"It's been two years since I've played against them." he said. "I'm studying this team all week and getting to know them.
Obviously I think you learn during the week and you learn during the game as well.
"I know they're creating a lot of turnovers. I know they've had chances to win and easily could be 4-0 at this point.
They're coming off a huge road win in the division in typical Patriots' fashion. It's always tough when you play them in Foxborough."
Elsewhere in week five, the unbeaten Atlanta Falcons have a challenging test in D.C. where they face Robert Griffin III and the Washington Redskins.
The Philadelphia Eagles (3-1) take on the Pittsburgh Steelers (1-2) who are returning fresh from a bye-week.
On Monday night, the Houston Texans (4-0) are at the New York Jets (2-2) who are hoping to bounce back from their awful 34-0 home loss to the San Francisco 49ers.
- Indianapolis Colts
- Bill Belichick