ORCHARD PARK, N.Y. — Picturesque snow fell to the ground, then so did Christian McCaffrey. Inevitably the San Francisco 49ers dropped as well for a third straight defeat, 35-10, on Sunday night against the AFC East-clinching Buffalo Bills.

The 49ers’ upset bid had life until McCaffrey left with an unspecified knee injury on their second drive.

Things truly snowballed from there: Home fans celebrated the Bills’ ensuing barrage of touchdowns by flinging snowballs into the air, made possible by this weekend’s lake-effect storm and the 49ers’ overall ineptitude.

The 49ers responded by dropping the ball — the slick football — with lost fumbles charged to Kyle Juszczyk (at the 1-yard line), Brock Purdy (fourth-quarter-opening sack), and Deebo Samuel (fourth-quarter kick return, down 35-10).

The 49ers (5-7) are alone in last place in the NFC West for the first time since the 2020 season ended. On the heels of this defeat and last Sunday’s 38-10 rout in Green Bay, the 49ers return to Levi’s Stadium to host NFC North doormat Chicago (4-8) next Sunday at 1:25 p.m. ET in the Bears’ first game under interim coach Thomas Brown.

Last season, the 49ers overcame a three-game skid last season en route to the Super Bowl. This season’s much-maligned team has much less time with much greater injury issues. Five games remain to reverse course and chase down NFC West foes Seattle (7-5), Arizona (6-6) and Los Angeles (6-6).

McCaffrey, who missed the first eight games with Achilles tendinitis, officially was ruled out at halftime Sunday night. The second quarter was just underway, however, when he banged his knee on the icy turf on an 18-yard run to the Bills’ 30-yard line. He intentionally slid and surrendered for a 5-yard loss on his next and final carry, in what was his fourth game back from Achilles issues.

McCaffrey’s departure weakened a Week 12 lineup already lacking left tackle Trent Williams (ankle), defensive end Nick Bosa (oblique), cornerback Deommodore Lenoir (knee), left guard Aaron Banks (concussion) and defensive tackle Jordan Elliott (concussion), not to mention this season’s earlier casualties such as wide receiver Brandon Aiyuk, safety Talanoa Hufanga and defensive tackle Javon Hargrave.

The 49ers welcomed Purdy back from a one-game absence, and his throwing-shoulder issue did not appear to hinder him, at least no more than the Bills’ defense and the climate (28 degrees). He was 11 of 18 for 94 yards.

McCaffrey was off to his best start of the season, racking up 78 rushing yards on six carries (before his 5-yard loss upon exiting) and adding two catches for 14 yards.

The Bills went on a four-touchdown spree before the 49ers finally found the end zone, on a 15-yard run from Isaac Guerendo in the third quarter for a 28-10 deficit.

Once Josh Allen produced his third touchdown of the night (one pass, one reception, one run), the Bills Mafia broke into an “MVP” chant to serenade the childhood 49ers fan. Allen was pulled for Mitchell Trubisky early in the fourth quarter.

While Allen’s touchdown pass went to Mack Hollins for a 21-3 halftime lead, the seventh-year quarterback scored on his own for the Bills’ next two touchdowns — first on a lateral from Amari Cooper at the 9-yard line after a completion from Allen, then the Bills’ lead climbed to 35-10 on Allen’s 8-yard touchdown run early in the fourth quarter.

The Bills’ touchdown that truly sprung their rout was James Cook’s 65-yard sprint past a 49ers defense that was temporarily missing Fred Warner (cramps). That score made it 14-3, and it came on their series after McCaffrey’s exit (and after Jake Moody’s first of two missed field-goal attempts).

The 49ers impressively opened their second-half comeback bid until Juszczyk fumbled at the 1-yard line. Samuel set up that potential touchdown drive by returning the second-half kickoff 60 yards, a week after another lengthy kick return that was wiped out by a penalty.

McCaffrey’s exit opened the door for early-season sensation Jordan Mason, and he had racked up 78 yards on 13 carries while also being cleared from a potential concussion. Guerendo had 19 yards on four carries.

The 49ers turned their opening possession into a 3-0 lead via Moody’s 33-yard field goal. That was a fair payoff for a drive that opened with an 8-yard completion to George Kittle before an eventual, season-long 19-yard run by McCaffrey to the Bills’ 29-yard line.

But first, the game opened with the 49ers defense rebounding quickly from last Sunday’s faceplant in Green Bay. They denied the Bills a first down on this game’s opening series, starting with Maliek Collins’ tackle for no gain on the first snap.

Having lost four of six road games with only trips remaining to Miami and Arizona, the 49ers will not have a winning record away from Levi’s Stadium for the first time since they went winless in eight road starts in their 2018 season (4-12 overall).

Notes

— Cornerback Charvarius Ward returned from a four-game absence, the last three of which were on bereavement leave after his 23-month-old daughter’s unexpected death.

— Josh Dobbs served as the No. 2 quarterback for a second straight game, with Brandon Allen moving into the No. 3 role after starting last Sunday’s loss at Green Bay.

— Bills rookie running back Frank Gore Jr., the son of the 49ers’ all-time leading rusher, was not elevated from the practice squad. His father, a 49ers personnel advisor, indeed made the trip to Buffalo.

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