For the first time in this rivalry, Manning will be in a Broncos uniform as he takes on his biggest nemesis. However, the goal has not changed. With both the Patriots and Broncos looking to earn their third win of the season, the question remains if there will be another memorable prime-time game for the ages.
There have been plenty of memorable clashes between Manning and Brady, but which were the most memorable of the past decade?
Here are the five best games played between these rivals.
One of the more famous matchups in this rivalry happened five years ago, when the 8-0 New England Patriots traveled to Indianapolis to take on Peyton Manning and the Colts.
For the majority of the game, the Colts controlled time of possession and kept the lethal Patriots offense off the field.
In fact, they were up on the Patriots by 10 points with 10 minutes left in the game. Unfortunately for the Colts, their defense had to stop one of the greater offenses in NFL history on multiple occasions and couldn't provide enough stops to hold on to the victory.
With that win, the Patriots eventually continued toward an undefeated regular season.
Peyton Manning has been known over his career for many fourth-quarter comebacks, especially against Tom Brady.
One of the more famous games between Manning and Brady came back in 2003, a game that appeared to be out of reach after a dominant start by the Patriots offense.
However, Manning kept his team in the game until the very end, when the game was ultimately decided on a goal-line stop by Willie McGinest.
McGinest made a game-saving stop against Edgerrin James, who couldn't react after McGinest exploded through the gaping holes of the Colts offensive line.
This rivalry may be focused on both offenses, but defenses have ultimately made the difference in many instances during this decade-long battle for AFC supremacy.
This AFC championship game showdown was one of the more memorable games for both Brady and Manning.
Brady continued building his legacy as one of the greater quarterbacks in NFL history with another AFC title win and a Super Bowl appearance.
However, the majority remember this game as the worst postseason performance in Peyton Manning's career.
Despite holding the Patriots offense to a mere 24 points, the Colts only managed to produce 14 points on a day when Manning threw four interceptions in Foxboro.
The questions as to whether or not Manning could ever win the big game became a topic of discussion for years following this infamous game for the Colts quarterback.
Peyton Manning's most memorable game against Tom Brady must be during the 2007 AFC championship game, where he defeated Brady when it mattered most.
The Colts have been known for their comebacks before against the Patriots, but their comeback on this day was even more bizarre.
Down 21-3 to the Patriots, Manning knew he couldn't let this opportunity slip past him. He led the charge in the fourth quarter, and the Colts moved on to their only Super Bowl with Manning at the helm.
The most memorable game played between Brady and Manning was defined by a gutsy fourth-down call made by Patriots head coach Bill Belichick.
Known for taking chances in the most unlikely situations, Belichick decided to go for it on 4th-and-2 from his own 28-yard line.
The chances appeared to be in his favor, as the Colts defense hadn't stopped the Patriots consistently during the game.
However, they made the biggest stop of the game when needed, as the Patriots failed to secure a first down late in the game.
Manning made the Patriots pay with a touchdown pass a few plays later, keeping the Colts' undefeated season intact.