Mitchell, the 49ers' leading rusher as a rookie in 2021, had been sidelined since Week 1 with a knee sprain.
His position as San Francisco's leading back looked to have been taken by McCaffrey last month when the 49ers traded four draft picks to acquire the former All-Pro in a deal with the Carolina Panthers.
However, the pair split carries as the 49ers prevailed in primetime despite an uneven offensive performance. Mitchell carried the ball 18 times for 81 yards and McCaffrey 14 times for 38 yards and a touchdown, the latter also had four catches for 39 yards.
The 49ers finished with 157 yards on the ground but at an average of just 3.8 yards per carry, however, Mitchell is confident he and McCaffrey can take their rushing attack to great heights.
"At the end of the day, it helps both of us and like I said, year six and he's an unbelievable back," Mitchell said of McCaffrey's arrival. "I get to learn from him so I'm excited for it.
"We could be the best duo of backs in the league, in my opinion."
The 49ers' victory moved them to 5-4, trailing the Seattle Seahawks (6-4) by just half a game in the race for the NFC West title.
San Francisco's vaunted defense dominated and shut out the Chargers in the second half, and running back Austin Ekeler refused to blame the Chargers' injuries for their struggles.
"We got some of our guys who are down," Ekeler said. "I get it. That doesn’t matter. . . . No one really created today.
"We need more playmaking. We didn't have that in the second half. We can't just go out there and play hard. That doesn't win in the NFL."