On Thanksgiving night, the Green Bay Packers have the opportunity to do the Buffalo Bills a favor. A team that has suddenly won three games in a row and is closely pursuing the Bills in the AFC East. However, on Sunday, the Packers embarrassed the San Francisco 49ers at Lambeau Field, setting up a challenging matchup for the Bills.

Defending NFC Champions in a Tough Spot

The defending NFC champions, the Buffalo Bills, currently find themselves in a precarious position. Sitting in last place in the NFC West with a 5-6 record, they are only one game behind co-leaders Seattle and Arizona. But the 49ers, far from out of the race, have dropped back-to-back games and need to get back on track quickly.

Packers' Dominance over the 49ers

In Green Bay, the 49ers played without key players like QB Brock Purdy, LT Trent Williams, DE Nick Bosa, and CB Charvarius Ward. This showed as they managed just 11 first downs with Brandon Allen at QB, had three turnovers plus a turnover on downs, and allowed 169 rushing yards, including 106 and three TDs to Josh Jacobs. The defense committed nine penalties for 77 yards, a concerning trend.

The whole game was a disappointment, as coach Kyle Shanahan pointed out. When you have those penalties, can't stop the run, and have turnovers in the second half, it leads to an embarrassing defeat. Now, the 49ers come to Orchard Park angry and motivated, with four key players potentially returning.

Since Sean McDermott arrived in 2017, the Bills have never lost in the week after their bye, going 7-0. This year's bye came at a good time as some injured players benefited. TE Dalton Kincaid, WR Keon Coleman, and OT Spencer Brown could be ready to go against the 49ers.

49ers' Key to Victory: Christian McCaffrey

Whether Purdy plays or not, the 49ers need to get RB Christian McCaffrey going. After missing the first eight games, McCaffrey has not been the same player who was the 2023 NFL offensive player of the year. He is averaging just 49.7 yards rushing and 3.5 per carry with 13 catches for 132 yards and no touchdowns. Opposing defenses have tried to take away the run game and dare the 49ers to throw. They face light boxes at a low rate and stacked boxes at a high rate.

The Bills, in their base nickel defense, have been in a light box 52.2% of the time. This might be a chance for McCaffrey and his backup, Jordan Mason, to do some damage against a defensive alignment they don't see too frequently.

Matchup to Watch: Khalil Shakir vs Deommodore Lenoir

For the third week in a row, Bills WR Khalil Shakir will face an excellent slot CB in San Francisco's Deommodore Lenoir. Shakir had a good game against the Colts' Kenny Moore and the Chiefs' Trent McDuffie but Lenoir has been a tough opponent. He has a low passer rating against among slot CBs and allows a low number of snaps per reception. Shakir leads all NFL WRs in catch percentage and is second in yards after catch, so this is a crucial matchup for him.

Who Will Win?

If Miami loses Thursday, the Bills will have a chance to wrap up their fifth consecutive AFC East title. If Miami wins, the Bills need to take care of business. San Francisco's health will be a major factor. It's too early to know if Purdy, Williams, Ward, and Bosa can return, but if they do, the Bills' task will be more difficult. Still, the Bills are at home where they have a strong record since 2020.

Kickoff is set for 8:20 p.m. at Highmark Stadium. The Bills have opened as a 6.5-point favorite with a money line of minus-275 (bet $275 to win $100) and the 49ers at plus-225 (bet $100 to win $225). The over-under is 46.

You can watch the game on NBC via local stations in different areas or through online streaming services like NFL.com and the NFL mobile app. You can also subscribe to NFL+. On the radio, you can listen on SiriusXM satellite radio on channels 225 (Bills feed) and 226 (49ers feed), and on traditional radio through the Bills Radio Network stations across the state.