Peyton Manning is two touchdown passes away from matching Brett Favre for the NFL record, but the Denver Broncos are aware it might take more than a few flicks of the wrist to beat the San Francisco 49ers.

Two of the NFL's top teams since the start of 2012 meet Sunday night in Denver with Manning focused on keeping pace in the AFC West over making history.

Favre reached his record of 508 TD passes in 302 regular-season games while Manning is sitting on 506 entering his 246th contest, but it's the continuation of a demanding opening schedule that has the attention of the Broncos (4-1) and Manning.

Denver's first eight opponents averaged 10.75 wins a season ago, and the 49ers (4-2) were on the high end with 12. Since the start of 2012, the Broncos have the NFL's most regular-season wins (30) while San Francisco is tied with Seattle (27) for the best in the NFC.

"Two big games coming up," said Manning, who will face the AFC West-leading Chargers next week. "That's plenty to think about."

It wouldn't be surprising for another milestone pass to land in the hands of Julius Thomas. He's caught nine of Manning's 15 in 2014, putting him on pace to surpass Rob Gronkowski's 2011 single-season tight end record of 17.

Thomas caught two in Sunday's 31-17 road win over the New York Jets, while Manning went 22 of 33 for 237 yards and three TDs.

The 49ers were one of the teams said to be in pursuit of Manning following his 2011 neck surgery, and San Francisco coach Jim Harbaugh still has plenty of praise.

"Whenever he takes the field, he's just great all the time and that speaks volumes for the player that he is and continues to be," Harbaugh said. "Just keeps doing it and doing it and doing it. Great. Great with a capital 'G' at the highest level."

He might have to be in order to solve San Francisco's defense in his first meeting with the 49ers since 2009. San Francisco ranks second in the NFL behind Detroit in total defense, giving up just 287.2 yards per game despite not having Aldon Smith or NaVorro Bowman. It could be further stretched if linebacker Patrick Willis, who suffered a toe injury in Monday's 31-17 win at St. Louis, is unable to play.

Still, the defense's 5.9 yards per passing attempt comes in as a league low and could present the Broncos with their most substantial challenge yet.

"We've had a pretty salty schedule thus far," coach John Fox said. "And this week is no different."

Offensively, the 49ers hit their stride against the Rams with a season-high 432 yards and their first 30-point output of the season. Colin Kaepernick accounted for 343 through the air with three TDs on 22-of-35 passing to guide San Francisco to a third straight win.

"He had some pinpoint throws," Harbaugh told the team's official website. "Had some throws where he laid it in there perfectly. ... I thought he was really on his game tonight."

It hasn't been quite as easy to move the ball against the Broncos. They rank fourth in the NFL in total defense (318.2 ypg), fourth in yards per pass attempt (6.23) and fifth in yards per rush (3.31).

Kaepernick, who wasn't sacked last week, pointed to Von Miller's six sacks and DeMarcus Ware's four as something to be aware of after facing a St. Louis team that has one through five games.

"They have two great ends that can rush the passer well," Kaepernick said. "We're going to have to be ready for that."

The Denver defense's rushing mark might be the greatest concern for San Francisco, which hasn't had the same kind of success running on the road (3.6 yards per carry, 99.3 yards per game) as it has at home (4.7, 172.7).

The Broncos' rushing attack has different concerns with running back Montee Ball expected to miss a second game with a groin injury, though Ronnie Hillman filled in against the Jets with 100 yards on 24 carries -- both career highs.

The Broncos have gone without committing a turnover three times in five games, but their plus-1 differential is tied for 18th while San Francisco's plus-5 ranks sixth.

The 49ers have won the last two meetings as the teams have split a 12-game all-time regular-season series.