The Broncos are still smarting from two losses to the Pats last season, including one that ended their surprising playoff run in the Divisional round.
Here are four battles within the game that will decide who walks away with the victory and a 3-2 record, and which team falls to 2-3.
Fortunately for Denver, they have a solid backup at the center position, and one who just happens to be a former Patriot, Dan Koppen.
Koppen filled in nicely for the remainder of the Oakland game following Walton's injury, but playing against his former team he faces Vince Wilfork—one of the biggest and most destructive defensive linemen in all of football.
The 325-pound Wilfork swallows up opposing running backs. If the Broncos want to do anything on the ground, moving Wilfork off the ball will be essential.
Koppen will need help from either of the guards, Manny Ramirez or Zane Beadles, and the fact that he has only worked a little over 30 minutes of game time with Manning will make even the routine snap from center a major focus.
It remains to be seen whether the Patriots will match Devin McCourty or Kyle Arrington against Demaryius Thomas, but McCourty will likely draw the assignment.
Manning will look for short passes across the middle of the field to Brandon Stokley, Eric Decker and his tight ends, but if he takes a shot down the field, expect the target to be Thomas.
Thomas is averaging a little more than five catches and 81 yards per game and two touchdowns this season. He needs to have a solid game and make a couple of big plays down the field. Manning will be looking to do just that.
The Patriots have a high-powered offense, but tight end Rob Gronkowski is easily the most dangerous player for opposing defenses.
Gronkowski possesses a deadly combination of size and speed. The Broncos really don't have a defender who can stop him, but they must do their best to slow him down.
Brady is always looking in Gronk's direction. He has 19 catches on the season, 14 of which have resulted in a first down.
In two games against Denver last year, Gronkowski had 14 receptions for 198 yards and three touchdowns.
If he makes the catch in the open field, good luck bringing him down.
The biggest key to the Broncos pulling out a road victory will be putting pressure on Tom Brady.
Dumervil has 2.5 sacks on the season, one of which was a safety. In his career, Dumervil has brought the quarterback down behind the line of scrimmage 55 times.
The man who will be primarily responsible for blocking Dumervil on Sunday is the 6'8", 320-pound Solder.
It's common sense that letting Brady stand in a clean pocket and pick you apart with precision passing is a recipe for disaster.
The Broncos must do something to disrupt Brady's timing, and it starts with Dumervil.