It’s the latest setback in a frustrating season for the 2023 Offensive Player of the Year, who missed the Niners’ first eight games with Achilles tendonitis and hasn’t shown his usual explosiveness since returning. And it’s another blow to a team that has struggled with injuries all season, missing five starters against Buffalo and falling for the third straight game.

San Francisco (5-7) sits alone in last place in the NFC West standings, two wins behind division leader Seattle, and is in danger of missing the playoffs a year after losing to Kansas City in the Super Bowl.

“He’s one of the best running backs in the league,” quarterback Brock Purdy said. “When you lose him like that, I think it kind of loses some things on offense.”

McCaffrey took an awkward step left on a snow-covered field and almost immediately went down, resulting in a 5-yard loss. He walked to the sideline and was examined in the medical tent before limping toward the locker room. The Niners announced before the start of the third quarter that he would not return.

Shanahan said he believes McCaffrey injured his knee when he was tackled by Taylor Rapp at the end of an 18-yard run earlier in the drive.

“It looked like he was just sweating it out there and was about to cancel a house call,” Shanahan said. “It was frustrating. He had a great week of training. I could feel his urgency and stuff. I thought it came out great and looked really good.”

McCaffrey’s 19-yard run in the first quarter was his longest of the season, and he had seven carries for 53 yards and two catches for 14 yards before getting injured.

“He was on fire, man,” Purdy said. “He looked great, hitting the holes hard, bouncing off guys and making some great plays.”

In a game played in wintry conditions and snowing throughout the night, very little went right for the 49ers.

Jake Moody missed two of three field goal attempts. San Francisco lost three fumbles, including fullback Kyle Juszczyk having the ball knocked out of his arms at the Buffalo 1, ending San Francisco’s first drive of the second half.

Star linebacker Fred Warner, who continues to play with a broken ankle, also left the game with cramps and was receiving intravenous fluids when James Cook scored on a 65-yard run to give the Bills a 14-3 lead.

“Demoralizing,” said Warner, who returned to finish the game. “I felt like I was letting my team down when I went into the locker room and then this happened.”

The 49ers found success in snowy conditions, rushing for 153 yards. JP Mason had 73 yards on 13 carries and Issac Guerendo ran for a 15-yard touchdown in the third quarter.

“Our goal was to give the best to the football and keep Josh Allen off the field,” tight end George Kittle said. “And I think we did that really well. But we have to get points.”

Kittle had a 7-yard reception on the 49ers’ first play of the game, but did not catch another pass in the game.

“It feels dark and gloomy and absolutely depressing,” Kittle said. “Football is a tough man. Things happen and you either allow them to fade you into oblivion and just give up, or you keep going out there and swinging and fighting every day you have left.”

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Freelance writer Jonah Bronstein contributed.

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AP NFL: https://apnews.com/hub/nfl