The decision to undergo surgery comes with a longer timeline than trying to rehab but is likely better for the long-term for Mostert, who is set to be a free agent in 2022.
NFL Network's Tom Pelissero reported that Mostert will undergo cartilage repair surgery and is looking at a roughly six-month recovery.
Mostert's agent, Brett Tessler, told Pelissero: "We decided to take the best option for his long-term health. We expect that he'll be back next season at 100 percent."
It's a brutal end to the nascent season for Mostert, who was in line for the lead role in the Niners backfield. The back looked great in his only two carries of the season, scampering for 20 yards. Alas, that is all the action the 29-year-old will see this season after suffering the knee injury. He played just eight games in 2020 while dealing with injuries.
With Mostert out Sunday, the Niners leaned on rookie Elijah Mitchell, who galloped for 104 yards on 19 carries (5.5 YPC) and a TD. JaMycal Hasty played the reserve role toting one time for a 3-yard TD and catching one pass for 15 yards.
Mitchell projects as the lead back in Kyle Shanahan's run-friendly scheme. The injury to Mostert also means rookie Trey Sermon, who was inactive on Sunday, should be in the lineup. The third-round rookie should get a chance to slice off a piece of the workload starting in Sunday's bout against the Philadelphia Eagles.
NFL Network's Mike Garafolo also reported the 49ers signed running back Kerryon Johnson to their practice squad. The move was later announced by the team.