This could be the final postseason matchup between these future Hall of Fame signal-callers, and the stakes couldn't be higher with a trip to Super Bowl XLVIII on the line in Denver.
Manning was the story of the season as he dissected NFL defenses with ease for 55 touchdown passes. Brady set the previous mark of 50 in 2007 when the Patriots nearly completed an historic 19-0 season before an upset loss in the Super Bowl to a New York Giants team led by Manning's brother, Eli.
Brady has won 10 of 14 matchups with Manning's teams, including a 2-1 mark in the postseason in which the home team has prevailed each time. This duel is drawing comparisons to other iconic sports matchups such as Ali-Frazier, Palmer-Nicklaus and Bird-Magic.
"It's going to a barnburner," Broncos executive vice president of football operations John Elway said.
The first meeting this season certainly was a thriller, as New England (13-4) rallied from a 24-0 halftime deficit for a 34-31 overtime win Nov. 24 in Foxborough. Manning was held to 150 yards, a 52.8 completion percentage and a 70.4 passer rating - by far his worst figures of his historic season.
Denver (14-3) is favored this time as the No. 1 seed with home-field advantage. Brady, who returned to practice Thursday after sitting out Wednesday because of illness, said in his weekly WEEI radio show that he is relishing being the underdog.
''I'm sure no one's going to pick us to win this week," said Brady, who will make his eighth AFC title game appearance and third in as many years. "We've had our backs against the wall for a while. Really, the whole season we've lost players, and teams have really counted us out."
The players that Brady and Manning will hand off to this weekend figure to be crucial in determining the winner.
Elway had Terrell Davis in his backfield when Denver won the Super Bowl in the 1997 and 1998 seasons, and Manning also will give the ball to a former Georgia tailback.
Knowshon Moreno had a career-high 1,038 rushing yards this season, and the Patriots will be very familiar with him after he had a career-best 224 yards in the November meeting.
Moreno's 23 carries for 82 yards along with a touchdown last Sunday helped Denver enjoy over 35 minutes of possession in a 24-17 divisional victory over San Diego. He had offseason knee surgery after being limited to 15 games over the past two seasons and now is one game away from a trip to the Super Bowl that will be about an hour's drive from Middletown, N.J., where Moreno grew up.
''He has just been a rock for us back there,'' Manning said.
While New England knows what to expect from Moreno, Denver can't say the same about LeGarrette Blount, who had two carries for 13 yards the last time these teams met.
Blount is rolling now with a career-high 189 rushing yards in a 34-20 win over Buffalo in Week 17, and 166 with four TDs in last Saturday's 43-22 rout of Indianapolis.
"I think they do a good job with personnel and he's obviously another different weapon but he's big and physical," Denver coach John Fox said. "He's got skins on the wall in this league as far as a running back."
The emergence of a New England running game that also features Stevan Ridley has taken the pressure off Brady, who was sacked 40 times this year for his highest total since 2001. One of Brady's best efforts came against Denver, as he completed 34 of 50 passes for 344 yards, three scores and no interceptions.
Brady has mostly been without his top five targets of 2012, with Wes Welker having departed to Denver and Rob Gronkowski limited to seven games before season-ending knee surgery. Julian Edelman has stepped up with a team-high 1,056 yards.
"I think he's really led our receiving group with a tremendous amount of toughness, consistency," offensive coordinator Josh McDaniels said. "He practices hard, prepares hard, he's on top of his game plan."
McDaniels will return to Denver for the first time since he posted an 11-17 record as Broncos coach before he was fired during the 2010 season.
Manning will be able to target tight end Julius Thomas, who missed the first meeting with a knee injury. Thomas had a team-high 76 yards through the air last weekend on six catches, converting a key 3rd-and-17 in the closing minutes to help seal the win.
"Excellent player - size, speed, he's a good vertical receiver, he gets down the field on seams and flags and over routes and wheel routes, like he caught last week and things like that," New England coach Bill Belichick said. "He's also good on catch-and-run plays."
Welker will try to atone for his gaffe in the first meeting when he failed to inform his teammates in time that he was not going to field Ryan Allen's punt in overtime. Teammate Tony Carter ran into it, and the Patriots recovered the ball to lead to Stephen Gostkowski's 31-yard field goal with 1:56 left.
Allen hurt his shoulder in the second quarter against the Colts, with Gostkowski punting the rest of the game. Allen returned to practice Wednesday, but Belichick did not say who will handle the punting duties.
The home team has won all three previous playoff meetings. Elway guided the Broncos to a 22-17 win after the 1986 season en route to his first Super Bowl appearance, Brady suffered his first loss in a playoff game after starting 10-0 with a 27-13 defeat after the 2005 season and the Patriots cruised to a 45-10 win two seasons ago against an overmatched Tim Tebow-led Denver squad.