The Panthers, who had a chance to take sole possession of the NFC South with a win, fall to 6-6 on the season.
McCaffrey, the league leader in scrimmage yards, now has 1,439 on the year with 12 total touchdowns.
"It was a great win," McCaffrey said. "But I know we're hungry for more and I know we can be better."
First half
The first half between the Panthers and 49ers was nothing but a turnover feast.
San Fan QB Brock Purdy tossed three interceptions on 14-of-23 passing for 114 yards. Two of Purdy's interceptions came from cornerback Jaycee Horn, who became the NFL's highest-paid cornerback in its history for a brief period this past offseason - money well spent.
Purdy did, however, throw a touchdown to Jauan Jennings, for the only one of the first half.
It was Purdy's eighth touchdown of the year and Jennings' fourth.
Panthers QB Bryce Young didn't have himself a much better half either. After the Panthers got down to the San Fran goal line, Young threw an interception in the end zone.
It's Young's seventh interception on the season and defensive back Ji'Ayir Brown's first - the fourth of his career.
Ryan Fitzgeral hit a 25-yard field goal for the Panthers, while Matt Gay hit a 47-yarder for the 49ers.
San Fran outgained the Panthers 180-72 in the first half, recording no penalties. They put up 13 first touchdowns in comparison to Carolina, who only managed three the entire half.
The Niners' offence was on the field for 39 plays, while Carolina was on there for just 19. Neither team recorded a sack in the first half.
Second half
49ers started the second half with their second and final touchdown of the game to take a commanding 17-3 lead.
McCaffrey capped off the 13-play, 80-yard drive with a 12-yard touchdown run.
In the very next drive, the Panthers finally found the endzone for the first, and only, time in the game to cut the to 17-9.
After a 29-yard touchdown pass to Tetairoa McMillan, the Panthers failed to convert on the two-point conversion, ending their scoring the night.
At the start of the fourth quarter, San Fran kicked another field goal to take the 20-9 lead.
Carolina would have a chance to cut it again, but Brown picked off Young for the second time on the night, leaving the Panthers hopeless for a comeback.
The Panthers would finish the game with 12 first downs, 230 yards, four penalties, and two turnovers.
Running back Rico Dowdle was held to a season-low 38 rushing yards since becoming the starter, but led the team with 36 receiving yards.
Young finished the game with 169 passing yards, one touchdown, and two interceptions on 18-of-29 passing, a week removed after almost reaching 500 passing yards.
Carolina will head back home to get ready to take on a red-hot Los Angeles Rams team led by MVP-favourite Matthew Stafford.
San Fran finished with 340 total yards, only two penalties, three turnovers, and 23 first downs.
Purdy finished with 193 yards, one touchdown, and three interceptions on 23-of-32 passing.
They'll head to Cleveland for their matchup against the Browns on November 30th.