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.

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.

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.

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.

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. The wide receiver caught the ball in front of cornerback Tramaine Brock on the left side of the end zone.

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 had 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 to him 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.

Manning connected with Welker, who dashed down the left sideline after the catch and dived into the end zone as he was being hit near the goal line by safety Antoine Bethea. The officials on the field ruled that Welker got the ball inside the end-zone pylon before being knocked out of bounds. The judgment was confirmed by replay review.

Sanders, an offseason free agent acquisition, caught his first touchdown pass from Manning on a slant route after 49ers defensive back Dontae Johnson ran into umpire Mark Pellis as he was giving chase to Sanders.

NOTES: San Francisco rookie LB Chris Borland made his first career start in place of Patrick Willis, who was inactive because of a toe injury. … 49ers C Daniel Kilgore was carted off the field in the third quarter, leaving with a leg and ankle injury. … The Broncos shook up their offensive line prior to the game, benching RT Chris Clark in favor of Paul Cornick. … A 9-foot bronze statue of Broncos owner Pat Bowlen was unveiled in the Ring of Fame Plaza at Sports Authority Field at Mile High. Bowlen, whose Broncos teams have gone to six Super Bowls and won two in his 31 years of ownership, is battling Alzheimer’s disease and has stepped down from an active ownership role.