SANTA CLARA, Calif. — As the San Francisco 49ers departed Buffalo in the wee hours Monday morning, they were bracing for the possibility that running back Christian McCaffrey had played his final game for them this season because of a right knee injury.

What the Niners didn’t know then was that not only were they going to lose McCaffrey for the season’s final five games but that Jordan Mason, McCaffrey’s backup, was also likely finished for 2024.

On Monday afternoon, all of that became the Niners’ new reality as coach Kyle Shanahan announced that McCaffrey’s posterior cruciate ligament injury would keep him out for about six weeks and that Mason suffered a high ankle sprain in the 35-10 loss to the Buffalo Bills. Both players are expected to land on injured reserve, according to Shanahan.

Shanahan said McCaffrey won’t need surgery but lamented the loss of a player who was rounding into form after missing the first eight games with bilateral Achilles tendinitis.

Suddenly, the Niners’ starting running back on Sunday against the Chicago Bears will be rookie Isaac Guerendo with practice squad back Patrick Taylor Jr. expected to be promoted to the 53-man roster and another back likely to be added.

McCaffrey was in the midst of his best game of the season Sunday night against the Bills, posting 53 yards on seven carries before leaving a few plays after banging his right knee on the Highmark Stadium turf when Bills safety Taylor Rapp narrowly prevented him from breaking a long touchdown run. McCaffrey briefly left the game, returned with 11:23 left in the second quarter and then promptly took himself out after he slid down on a toss to the right for a loss of 5 yards.

After McCaffrey departed, Mason capably filled in, much like he has all season. Mason had 13 carries for 78 yards against Buffalo, despite the ankle injury and, at one point, being evaluated and cleared for a concussion.

Mason finishes his season while leading the Niners in rushing with 789 yards and three touchdowns through the team’s first 12 games. McCaffrey posted 202 rushing yards and no touchdowns in his abbreviated action. Mason is set to be a restricted free agent after the season with McCaffrey under contract at a cap charge of $9.8 million for 2025.

Guerendo, a fourth-round pick out of Louisville in April, scored San Francisco’s lone touchdown against the Bills and has, at times, offered promise in the run game with his home run speed. On 42 attempts, Guerendo has 246 rushing yards on the season (5.9 yards per carry) to go with a pair of touchdowns.

Elsewhere on the injury front, Shanahan said cornerback Deommodore Lenoir (knee) is expected to return to practice Wednesday after not playing against Buffalo. Defensive tackle Jordan Elliott and guard Aaron Banks are still in the concussion protocol while defensive end Nick Bosa (left oblique) and offensive tackle Trent Williams (left ankle) will be evaluated day to day for the third consecutive week.

Shanahan also announced that safety Talanoa Hufanga (wrist) will open his practice window this week as he continues to work his way back from IR.

Meanwhile, defensive tackle Kevin Givens will be placed on IR after suffering a torn pectoral against the Bills.