They'll open the playoffs against a Baltimore Ravens team looking to avenge a regular-season loss to the Broncos and prolong the career of their own future Hall of Famer.
Trying to help the Broncos to a 12th straight victory, Manning looks to continue his success against the visiting Ravens and Ray Lewis, who could play his final game in Saturday's divisional matchup.
Sidelined the entire 2011 season following a series of neck surgeries, Manning has even surprised himself by recording an MVP-worthy year in his first with Denver (13-3). The 36-year-old four-time MVP was tied for first in the league in completion percentage (68.6), finished second in passer rating (105.8), third in touchdowns (37) and sixth in yards (4,659) for a team that averaged 30.1 points and won its last 11 games to claim the top seed in the conference.
The run is the team's longest since an 18-game winning streak Dec. 21, 1997-Dec. 6, 1998, that included playoffs.
"It's been quite a year for me," Manning told the Broncos' official website. "I remember one year ago I was in a hospital bed watching opening day, so there's a little reminder there of how far I've come."
It would seem fitting if Manning could complete this improbable journey by hoisting the Lombardi Trophy in his native New Orleans on Feb. 3. The next step to getting there is winning his first playoff game since his last with Indianapolis, a 17-16 loss to the New York Jets on Jan. 8, 2011.
Manning and the Broncos have had two weeks to prepare for Baltimore (11-6), a 24-9 winner over the Colts on Sunday in Lewis' final home game before his pending retirement after 17 seasons.
Manning has won nine straight overall versus the Ravens, including two playoff matchups despite throwing three interceptions with two touchdowns and posting a 68.3 rating in the postseason games.
He was 17 of 28 for 204 yards with a touchdown in a 34-17 win at Baltimore in Week 15. Lewis, safety Bernard Pollard, guard Marshal Yanda and tight end Ed Dickson missed that contest, but all are now healthy.
Two of the game's finest butting heads for the final time will dominate the headlines, but Manning would rather keep his respect for Lewis private.
"I think Ray Lewis knows how I feel about him and I think I'll share that with him at the appropriate time," he said.
Lewis' focus is on helping Baltimore reach the AFC championship game for a second straight season.
"It's just one of those chess matches," said the two-time Defensive Player of the Year, who recorded 13 tackles Sunday in his return from a torn triceps that sidelined him for 12 weeks. "(Manning) knows me very well. I know him very well. ... But at the end of the day, it's not about me and me and Peyton. It's about their team against our team.
"I love our team right now.''
After totaling 441 yards and limiting star rookie Andrew Luck and the Colts to three field goals, the Ravens are only looking forward and not concerned about last month's loss to Denver.
"We all have a goal in mind, and we're focused in on that goal,'' said receiver Anquan Boldin, who caught five passes for a franchise-high 145 yards and a touchdown last week.
The Broncos also expect to face a better team than the one that managed 278 yards in the December matchup.
"It means nothing that we beat them in the regular season," said Denver receiver Brandon Stokley, a member of the Ravens when they beat the Broncos 21-3 in a wild-card game during their 2000 Super Bowl season. "I know we beat them pretty good, but in the playoffs it's just a different game."
Though the Broncos have homefield advantage, expected game-time temperatures in the low 20s may not bode well for them, as Manning is 0-3 in playoff games in which the temperature at kickoff is less than 40 degrees. He's a combined 64 for 120 for 612 yards with one TD and seven INTs in those contests, and will play with a glove on his throwing hand.
Manning, who hasn't worn anything on his hands before this season, conceded the glove is a concession to the altered feel of his grip, especially in cold weather, after his neck surgeries.
For that reason, the Ravens could again receive a steady dose of Knowshon Moreno, who ran for 115 yards and a TD against them last month. Even with Lewis in the lineup, the Ravens allowed 152 rushing yards last week.
Denver has yielded 237.3 total yards and 13.5 points during a six-game home winning streak.
"You just have to be ready to go into a hostile environment and play your best football," said quarterback Joe Flacco, who's 2-1 against the Broncos but is facing them on the road for the first time.
Baltimore's Ray Rice, who lost two fumbles last week after losing one during the regular season, was held to 38 yards on 12 carries against the Broncos in Week 15. He's averaged 58.8 yards and scored one rushing TD in his last six postseason contests.
Flacco improved to 2-0 at home in the playoffs by throwing for 282 yards with two TDs and no interceptions against the Colts. However, he's lost his last two postseason road contests, passing for 431 yards with three touchdowns and two picks.
Flacco was 20 of 40 for 254 yards with two TDs and one INT versus Denver last month.
The former Super Bowl champion and the postseason newcomer will be in the spotlight and can expect to face tough defenses Saturday night when the Packers visit the 49ers in a marquee NFC divisional playoff contest.
Rodgers is from Chico, about a three-hour drive north of the Bay Area. The only time he has played at San Francisco is in the preseason, and the former 49ers fan was overlooked by them in the 2005 draft with Alex Smith going No. 1.
"Home is really Chico," said Rodgers, who produced an NFL-best 108.0 passer rating. "Chico I would say is in northern California, San Francisco I would say is Bay Area. So it'll be fun to go back to the West Coast, a lot of people in the area, hopefully get a lot of cheeseheads from Chico coming down to the game and it'll be a good test."
Smith, meanwhile, led the second-seeded 49ers to last year's NFC title game but has been replaced by Kaepernick, who was born in Milwaukee and went 5-2 as the starter. Kaepernick said he rooted for the Packers (12-5), and that he's not in awe of his first playoff opportunity even though he's going up against the reigning league MVP.
"Aaron Rodgers is a great quarterback," Kaepernick said. "You see what he does on the field and you see performances he's been having, so you can't say enough about the guy. We're going to have to go out and put up points."
Kaepernick's emergence as a starter is one of many changes since these teams met in the season opener as the 49ers (11-4-1) posted a 30-22 road victory. Smith completed 20 of 26 passes with two scores.
While Smith was mostly a stationary target and was sacked four times, Kaepernick's mobility gives the Niners a completely new look. Kaepernick had a 17-yard carry in the opener and did not throw a pass.
"Colin Kaepernick just for the little time he has been a starter, is a lot more experienced, a lot more productive quarterback," Packers coach Mike McCarthy said. "He creates different challenges for us."
The Packers had a healthy Cedric Benson back then, although he was bottled up for 18 yards on nine carries. Benson is out for the season, and undrafted DuJuan Harris is now the starting back after rushing for 47 yards in last Saturday's 24-10 wild-card victory over Minnesota.
Although the 49ers finished around the middle of the pack with 38 sacks - Aldon Smith had an NFC-high 19 1/2 - their pass rush figures to be a major factor against Rodgers, who was sacked a league-high 51 times including three in the opener.
"There's no other defense we'd rather go into a game than ours," coach Jim Harbaugh said.
That defense figures to gain a boost with the return of tackle Justin Smith, who missed the last two games with a partially torn triceps tendon. He has been practicing this week for the 49ers, who yielded an NFC-low average of 311.3 yards in the regular season.
"I think it's just a matter of getting out there and going," Justin Smith said. "I think like I said you just go out there and play until you can't and be ready. I feel like I'll be ready."
The Packers' defense will be facing another tough rushing attack after limiting Adrian Peterson to 99 yards last week. Green Bay may be helped after facing backup Vikings quarterback Joe Webb, who ran for 68 yards and presents a similar threat on the ground as Kaepernick.
While Minnesota ranked second in the NFL with 164.6 yards per game on the ground, San Francisco was fourth at 155.7. Niners back Frank Gore had 1,212 yards, with 112 coming in the opener.
Green Bay has been bolstered by the return of star linebacker Clay Matthews, who has played the last four games after missing four with a hamstring injury. Former Defensive Player of the Year Charles Woodson returned last weekend after the cornerback was out since Oct. 21 with a collarbone injury.
Woodson should play a key role in trying to slow down Michael Crabtree, who has become Kaepernick's favorite target with 35 catches for 538 yards in five December games. Crabtree also had four of his team-high nine touchdown receptions in that span.
Vernon Davis became a virtual non-factor once Kaepernick took over, with a combined 61 yards and no TDs over the last six games. However, the tight end has scored in all four games he's played against the Packers, totaling 351 yards, and he had 10 receptions for 292 yards with four TDs in two postseason games last year.
"I'll just wait for my opportunities. I'm sure they will come," Davis said. "I said the same thing last year, even though I didn't get the ball as much as I wanted last year, I said my opportunities will come. And maybe I'll get them this week."
The change to Kaepernick was made partially because the Niners struggled offensively in their 20-17 loss to the Giants in last year's NFC title game. The Packers lost to New York in the previous round after a 15-1 season.
Green Bay may not be the more rested team, but that didn't matter two seasons ago when it was seeded sixth and Rodgers guided them to three road wins and a Super Bowl triumph over Pittsburgh.
"It's just something we know," offensive lineman Josh Sitton said. "We have confidence in each other, and we feel we could go win anywhere."
The Packers are 4-1 in the postseason against San Francisco.
The Niners could have a new kicker Saturday after signing Billy Cundiff last week since David Akers has missed seven of his last 18 field-goal attempts. Cundiff, cut by Washington this season after making 7 of 12 attempts, missed a potential game-tying 32-yard attempt in last year's AFC title game for Baltimore against New England.
Akers converted 69.0 percent of his field-goal tries, with only Green Bay's Mason Crosby lower at 63.6. Crosby, though, has made all four over the last two games, including three of 40 yards or more.