The September 9 game, announced by the NFL along with the full 2012 schedule, will be the first in 20 months for the four-time Most Valuable Player, who was cut by the Indianapolis Colts in March after missing the 2011 campaign recovering from neck surgery.
"The opening game in Denver obviously will be an interesting way to start the season," Steelers' president Art Rooney said.
"There will be a lot of attention paid to Peyton Manning's first game with the Denver Broncos, so it'll be exciting to start out that way."
Plenty of attention on the first Sunday of the season will also be paid to the New Orleans Saints when the scandal-ravaged team hosts the Washington Redskins, who are expected to draft Heisman Trophy-winning quarterback Robert Griffin III next week.
Saints coach Sean Payton is suspended the entire season for his part in a scheme that paid bonuses to players for knocking opponents out of games, several players could still be banned and quarterback Drew Brees is dealing with a contract dispute.
Tim Tebow, who was released by the Broncos to make way for Manning, could make his Big Apple debut when the New York Jets host the Buffalo Bills in Week One.
Opening week will also feature a Monday Night double-header with the Cincinnati Bengals visiting the Baltimore Ravens and the Oakland Raiders hosting the San Diego Chargers.
"From our team's standpoint and our fans' standpoint, I don't know that you could put together a more exciting schedule when you look at the number of great teams we play and when we play them," Chargers head coach Norv Turner said.
"We start our offseason program on Monday and I think it really gives our guys something to look forward to. It should give our guys great motivation."
The Green Bay Packers and Chicago Bears will add another chapter to their long-standing rivalry when they open Week Two with a Thursday meeting at Lambeau Field, while defensive end Mario Williams, who left the Houston Texans to join the Buffalo Bills in the biggest off-season signing after Manning, makes his home debut against the Kansas City Chiefs.
Williams, the NFL's highest-paid defensive player, will face his former team when the Bills visit the Texans on November 1 for a Week Nine game.
The U.S. Thanksgiving Day lineup will see familiar names suiting up Nov. 22 as Tom Brady and the New England Patriots visit the rival New York Jets, Houston heads to the Motor City to face the Detroit Lions and the Dallas Cowboys host Washington.
Two games will be played outside the United States as the St. Louis Rams and Patriots play at London's Wembley Stadium on October 28 while the Buffalo Bills make their annual visit to Toronto for a December 16 game against the Seattle Seahawks.
The NFL had already announced that the regular season will kick off September 5 with the Super Bowl champion New York Giants hosting the division rival Dallas Cowboys.