Manning threw four touchdown passes, including three in the first half to surpass former Green Bay Packers QB Brett Favre on the all-time list, as the Broncos won 42-17 in Denver.
With just over three minutes left in the second quarter, Manning picked out Demaryius Thomas in the end zone with an eight-yard throw to register the 509th TD pass of his NFL career.
The Broncos claimed top spot in the American Football Conference (AFC) West division, while the Dallas Cowboys moved a game clear of the Philadelphia Eagles in the National Football Conference (NFC) East standings.
At Mile High Stadium in Colorado, Manning started the rout of the 49ers midway through the first quarter, finding Emmanuel Sanders in the end zone to give the Broncos the lead.
Wes Welker was the next to benefit from Manning's quality, catching the 38-year-old's pass on the sideline and then sprinting the last 20 yards to complete a 33-yard TD reception with 2:57 on the clock in the opening term.
After San Francisco scored a field goal in the second quarter, Thomas caught the record-breaking pass to help the Broncos to a 21-3 lead, although the visitors hit back with 11 seconds remaining in the half when 49ers quarterback Colin Kaepernick found Stevie Johnson for a touchdown.
But just over three minutes into the second half, Manning threw a 40-yard pass to Thomas for Denver's fourth TD, effectively ending the contest, while Ronnie Hillman rushed for two more six-pointers in the third period, as the Broncos notched a 25-point win.
Manning sat out the fourth quarter, finishing the game with 22 completed passes from 26 attempts for a total of 318 yards.
Denver (5-1 win-loss record) lead the AFC West from the San Diego Chargers (5-2) and the Kansas City Chiefs (3-3), while the Oakland Raiders (0-6) are bottom of the division.
Kansas City defeated San Diego 23-20, while Oakland went down to the Arizona Cardinals 24-13.
In Texas, Dallas scored a touchdown in every quarter to hold off the New York Giants in a 31-21 victory.
Gavin Escobar received two TD passes from Cowboys quarterback Tony Romo, while Odell Beckham did the same for the Giants from Eli Manning.
The Cowboys registered their sixth win from seven games to edge ahead of Philadelphia in the NFC East, with the Eagles having a bye this weekend.
The Giants (3-4) are third, while the Washington Redskins (2-5) are fourth after knocking off the Tennessee Titans 19-17.
The Indianapolis Colts thrashed the Cincinnati Bengals 27-0 to strengthen their hold on top spot in the AFC South, while the AFC North-leading Baltimore Ravens cruised past the Atlanta Falcons 29-7.
The St Louis Rams edged out the Seattle Seahawks 28-26, the Jacksonville Jaguars claimed their first win of the season, overcoming the Cleveland Browns 24-6 and the Buffalo Bills defeated the Minnesota Vikings 17-16.
The Miami Dolphins won 27-14 over the Chicago Bears, the Detroit Lions overhauled the New Orleans Saints 24-23 and Green Bay thrashed the Carolina Panthers 38-17.
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