DENVER — Peyton Manning wasted no time making history Sunday night, and there wasn’t much the San Francisco 49ers could do about it.

The Broncos quarterback, who fought back from a career-threatening neck injury four years ago, threw four touchdown passes to push his career total to an NFL-record 510, leading Denver to a 42-17 victory over the 49ers.

“It was a special night, I think certainly more special because of the way our team played and because we got the win,” Manning said. “Such a team effort. It’s definitely one I’ll always remember.”

Manning was on the money with his passes from the outset as the Broncos built a 21-10 halftime lead behind his first three touchdown throws, including the record-setting 509th to wide receiver Demaryius Thomas with 3:09 left in the second quarter.

“He played at the highest level, real excellence,” 49ers coach Jim Harbaugh said. “In all phases, the Broncos were on their game, especially Peyton. Congratulations to him on breaking the record.”

Manning, lifted after three quarters in favor of backup Brock Osweiler with the Broncos leading 42-10, was just too much for a San Francisco defense that came in with an injury-depleted secondary. He finished with 318 passing yards, completing 22 of 26 throws.

Thomas caught eight passes for 171 yards and two touchdowns.

“Definitely didn’t see it coming,” Manning said. “San Francisco is a great opponent. They have some injuries that I think put some pressure on their defense, and we were able to take advantage of it.”

And they did it in record-setting fashion.

The Broncos (5-1) moved a half-game ahead of the San Diego Chargers (5-2) in the AFC West. San Francisco (4-3) fell 1 1/2 games behind the Arizona Cardinals (5-1) in the NFC West.

“We have to be better than that,” 49ers tight end Vernon Davis said. “We have to be better than that, and we can. We have the guys to do it. We just have to keep our focus and keep going.”

Denver’s defense chipped in for the big win with a stout effort against quarterback Colin Kaepernick, who was sacked six times, including three times by defensive end DeMarcus Ware and twice by linebacker Von Miller.

Manning snapped a tie with the previous record-holder, Brett Favre, when he arced an 8-yard pass to Thomas on a third-and-goal play. The wide receiver caught the ball in front of cornerback Tramaine Brock on the left side of the end zone.

“Wasn’t feeling real great on that third down,” said Manning, who threw an incompletion on his first try from up close and tripped and fell for a 7-yard sack on second down. “They dropped eight in coverage, which can be tough. But Demaryius ran a good route, put some pressure on that cornerback. I knew I had to get the ball outside just in case the corner was going to squat, and (Thomas) did a great job of keeping his feet in bounds.”

The record-breaking TD toss prompted a brief in-game celebration with teammates rushing to congratulate Manning. He even got a congratulatory pat on the helmet from 49ers linebacker Aaron Lynch, who sacked him earlier in the game.

San Francisco trailed 21-3 before breaking through for its first touchdown when Kaepernick finished off an 80-yard drive with a 4-yard pass to wide receiver Stevie Johnson with 11 seconds remaining in the second quarter.

Earlier, the 49ers settled for a 22-yard field goal by Phil Dawson after wide receiver Anquan Boldin couldn’t hold onto Kaepernick’s pass at the goal line.

Manning and Thomas teamed up again in the third quarter. On the first play after cornerback Aqib Talib picked off Kaepernick, Thomas got behind cornerback Perrish Cox on a go route, and Manning hit him in stride for a 40-yard touchdown.

Running back Ronnie Hillman put the finishing touches on the rout with scoring runs of 1 and 37 yards later in the third quarter. The shorter run was set up after the 49ers were called for pass interference in the end zone.

San Francisco backup quarterback Blaine Gabbert threw a 20-yard touchdown pass to wide receiver Bruce Ellington in the game’s final minutes.

Kaepernick completed 24 of 39 passes for 263 yards with one touchdown pass and one interception.

Manning moved to the cusp of the record after first-quarter scoring passes of 39 yards to wide receiver Wes Welker and 3 yards to wide receiver Emmanuel Sanders.

What the Broncos said:

“The crowd was electric from the jump. And just to be part of history and Peyton (Manning) breaking that record, I’m excited for him and I know he’s excited. He might not have talked about it during the week, but I know Peyton, and Peyton loves to play this game. He loves to break records and he loves to put up points. And he’s just happy he achieved it tonight, and I’m happy for him.” — Wide receiver Emmanuel Sanders, who caught the first of Manning’s four touchdown passes on a night when the Broncos quarterback became the NFL’s career leader in TD tosses.

What the 49ers said:

“Right now, it’s onward. We’ll rally. Our team will be good at that.” — Coach Jim Harbaugh.

What we learned about the Broncos:

1. Defensive end DeMarcus Ware still has a lot left after being let go by Dallas, and Von Miller is coming back strong after last year’s season-ending knee injury. The two have become one of the league’s top pass rushing tandems, and they combined for five of the Broncos’ six sacks against the 49ers.

2. Running back Ronnie Hillman had a productive outing as he continues to fill in for Montee Ball, who is out indefinitely with a groin injury. Hillman ran for 74 yards on 14 carries and had touchdown runs of 1 and 37 yards. His 37-yarder was the longest run against the 49ers’ defense since 2010.

–WR Demaryius Thomas had his third consecutive game with at least 100 yards receiving, tying a team record. He finished with eight catches for 171 and two touchdowns — the record 509th of QB Peyton Manning’s career, then Manning’s 510th. In his past three games, Thomas has 27 catches for 521 yards and five touchdowns.

–LB Von Miller had two sacks, extending his sack streak to five games. It is the longest active streak in the NFL.

–CB Aqib Talib’s interception of San Francisco QB Colin Kaepernick led to a Broncos touchdown. It was the 25th interception of his career and the third most in the NFL since he came into the league in 2008. Only Asante Samuel (29) and DeAngelo Hall (26) have more in that span.

What we learned about the 49ers:

1. Quarterback Colin Kaepernick had a rough night, but his receivers didn’t do him any favors either. Wide receiver Michael Crabtree had a couple of drops, and tight end Vernon Davis and wide receiver Anquan Boldin also had critical miscues. Chalk it up to a tough outing against a top-notch defense, but Davis conceded after the game, “We just have to be better.”

2. The 49ers are being hit hard by injuries, and how they respond will determine the course of the season going forward. On defense, they were missing stalwart linebacker Patrick Willis (toe) along with two of their top defensive backs. On offense, guard Mike Iupati missed the game with a concussion and center Daniel Kilgore left the game with what appears to be a serious leg injury.

–RB Frank Gore didn’t have much of a chance to run the ball, and when he did, he didn’t get very far. Gore was held to 20 yards on nine carries, an average of 2.2 yards per attempt.

–C Daniel Kilgore may have sustained a fracture when he went out with a leg and ankle injury in the third quarter, possibly a season-ending injury, according to coach Jim Harbaugh. Harbaugh said Dillon Farrell and Marcus Martin are candidates to replace him.

–QB Colin Kaepernick and Broncos QB Peyton Manning each started nine drives. Six of Manning’s ended with touchdowns. Only one of Kaepernick’s wound up in the end zone. Kaepernick completed 24 of 39 passes for 263 yards with one touchdown and one interception. He was sacked six times.