The veteran duo are two of the NFL's biggest stars, but at 37 and 38 respectively, there is little question the pair are in the twilight years of their glittering careers.
This weekend's repeat of last season's AFC Championship match sees Brady and Manning lock horns for the 16th time, and Brady is determined to savour the occasion.
"Five, six years ago you don't think about those things," he is quoted as telling WEEI-FM. "But as you mature a little bit and realise this could always be the last one, then you do. It's pretty special.
"[Manning has] been one of the greatest players to ever play. I've been fortunate to share a field with one of the best players that has ever played the game. And every time we play a Peyton Manning-led team, it comes down to the wire. Everything is usually at stake.
"What can you say more about what Peyton Manning has been able to accomplish?
"Nobody has really matched what he has been able to do, what that offense has been able to do most importantly."
The Broncos claimed a 26-16 victory to claim the AFC Championship back in January, before going on to be humbled 43-8 by the Seattle Seahawks in the Super Bowl.
Both sides look in excellent shape as the season enters its ninth week - the Broncos (6-1) topping AFC West, while the Patriots (6-2) sit at the summit in AFC East.
With two four-match winning streaks on the line, this weekend's clash promises to be an enthralling encounter.
The Miami Dolphins will be looking to join the Buffalo Bills on 5-3 in AFC East when they host the San Diego Chargers, while the New York Jets bid to end a seven-match losing run at Kansas City Chiefs.
Jets coach Rex Ryan has come under increasing pressure from the press, with the New York Post running the headline 'Fire Rex today!' earlier this week following a 43-23 defeat to the Bills.
Tony Romo's back injury will come as a blow to the Dallas Cowboys as they look to bounce back from their 20-17 defeat to the Washington Redskins last time out. They welcome the in-form Arizona Cardinals to AT and T Stadium.
A slip-up by the Cowboys could open the door for the Philadelphia Eagles - visiting the Houston Texans on Sunday - to equal their six wins for the season so far.
NFC South's Carolina Panthers will lose top spot to the New Orleans Saints unless they can call time on a two-match losing run.
The New York Giants are at home to the Indianapolis Colts, while the Washington Redskins are at Minnesota Vikings.
AFC North leaders the Cincinnati Bengals host the struggling Jacksonvile Jaguars, and the Pittsburgh Steelers welcome the Baltimore Ravens.
Elsewhere, the Tampa Bay Buccaneers visit the Cleveland Browns, the St Louis Rams are at the San Francisco 49ers, and the Seahawks host the Oakland Raiders.
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