San Francisco forced quarterback Kerry Collins to turn the ball over four times, including three interceptions, to win 34-21.
The Panthers, who beat the 49ers twice last season en route to the divisional title and NFC Championship game, suffered their third consecutive home defeat, which comes as a blow after last season, when they were unbeaten at home. The win increased the 49ers' lead over Carolina and St Louis to two games.
Running back Garrison Hearst ran for a career-best 141 yards and added a touchdown, while Merton Hanks picked off two Collins passes which led to 10 San Francisco points.
Collins fumbled in the second quarter with Carolina deep in 49ers' territory, and threw an interception to Hanks, later in the quarter.