Buffalo Bills vs. San Francisco 49ers predictions, picks, and game preview for Week 13 of the 2020 NFL season.

• Bills 49ers Prediction Green Bay Packers
• Bills 49ers Prediction Score

The Buffalo Bills will travel back to the scene of the crime on Monday as the San Francisco 49ers await.

Last weekend, the 49ers (5-6) won on a last-second play, which actually will make this one a bit more fun, won’t it? The Bills (8-3) also continued their march toward their first AFC East title since 1995. Huge and obvious playoff implications for both sides here.

Plus, the primetime lights on Monday Night Football will be shining bright.

🏈 Buffalo Bills vs San Francisco 49ers picks, predictions and odds for their Monday Night Football showdown on December 7, 2020, at 8:15 p.m. Fresh off a huge win over the Los Angeles Rams in Week 12, the San Francisco 49ers clash with the Buffalo Bills in the second game of a Monday Night Football doubleheader (Dec. 7, 8:15 pm EST). This contest will take place in Arizona, the Niners new home for the rest of the season, and has seen a pretty big line move at online sportsbooks. The Bills will play the San Francisco 49ers on a neutral field, State Farm Stadium in Arizona, and Sal Maiorana has the breakdown of the game. After escaping with a 27-17 win over the Los Angeles Chargers on Sunday, the Buffalo Bills look to next weekend’s road date with the San Francisco 49ers on Monday Night Football, perched as 3-point favorites in the NFL Week 13 opening odds.

With that, here are five things to watch for and a prediction ahead of Week 13’s Bills-49ers meeting:

Playing in Arizona

Cardinals play the visiting San Francisco 49ers. (AP Photo/Darryl Webb)

The scene of the crime mentioned is the Hail Murray from when the Bills faced the Cardinals in Arizona a few weeks ago. You’re going to see those images all over your TV on Monday, so prepare. We’ll see Buffalo head back there for the 49ers because of new COVID-19 related restrictions in San Francisco. They’ve been relocated for this one.

But in doing so, how does that affect the 49ers? And for those of us who like the novelty of the thing, do the Cardinals dress up the stadium at all for their guests? The 49ers and Cards are division rivals, after all. Imagine the Dolphins setting up Hard Rock Stadium for the Bills?

Playmaker battles

49ers wide receiver Deebo Samuel . (AP Photo/Tony Avelar)

Helping the 49ers upset the Rams in Week 12 was Deebo Samuel. The wideout had 11 catches and 133 receiving yards in his first game since Week 7. Who put up no stats against the Rams was Brandon Aiyuk as the rookie was placed on the 49ers’ Reserve/COVID-19 list for that outing.

Which means a marquee battle will be Samuel and Aiyuk vs. Tre’Davious White and Levi Wallace. White’s played all season as Buffalo’s No. 1 cornerback, but just last week was the first time in the entire year both Wallace and Josh Norman featured in a game without someone getting hurt or missing the game in general. The result was Wallace being Buffalo’s No. 2 cornerback, and he’ll have an important role this week.

Niners quarterback Nick Mullens will want to help his running game out by getting the ball to his playmakers outside, and as Samuel’s 11 catches show, Mullens can do just that. Take that away, the rest of the Bills defense can focus on the run.

How does D-line arrangement work?

Bills defensive end Trent Murphy. (AP Photo/Ross D. Franklin)

We’ll guess that the answer to this is AJ Epenesa and Harrison Phillips in with Trent Murphy out again. But how does the Bills defensive line vs. the 49ers look?

Murphy was scratched last week so Epenesa and Darryl Johnson could get more playing time. In addition, Phillips was brought back in the middle at tackle. The Bills bottled up the run really well last week against the Bolts and had constant pressure on quarterback Justin Herbert, leading to his worst game of the year.

Buffalo head coach Sean McDermott, as we’ve seen with the offensive line, very much believes in a… if it don’t broke, don’t fix it approach. That’s where our guess, of sorts, comes in.

Run game commitment?

Bills 49ers Prediction Green Bay Packers

Bills running back Devin Singletary. Credit: Rich Barnes-USA TODAY Sports

What’s going to happen with the run game… on offense? Against the Chargers, the Bills had their biggest commitment to it all season. Running backs Devin Singletary and Zack Moss took off and even quarterback Josh Allen got in on the designed carries. Buffalo had 172 total rushing yards.

More of the same vs. the Niners? Or do we see another Allen unleashing?

Top defense despite injuries

49ers free safety Jimmie Ward. Credit: Kyle Terada-USA TODAY Sports

Remember how the Patriots were hurt the most from opt outs this season due to COVID? Well the old-fashion way caught the 49ers more than anyone in 2020: The injury bug.

Pass rusher Nick Bosa, tight end George Kittle and quarterback Jimmy Garoppolo are among the many guys this team is missing due to injury. But despite that, they’ve still produced some solid games, as their record indicates. Specifically on defense, they’ve had some good, savvy players, keeping them in the playoff race.

Names to watch: CB Jason Verrett (PFF’s 5th best cornerback in 2020), S Jimmie Ward (7th), LB Fred Warner (5th), DE Arik Armstead (19th), and Richard Sherman (N/A).

Prediction: Bills 28, 49ers 17

While the 49ers got some playmakers back recently and still have a stout defense, the Bills have shown in 2020 they can beat a lot tougher opponents than the Niners. The 49ers offense thrives on the run game, especially since Mullens is pulling the strings, but in recent weeks, the Bills have shown their overall defense is improving. Run defense included.

Bills 49ers Prediction Score

Even if Allen doesn’t get a perfect run game to complement him on the opposite side of the ball, the Bills should have plenty of firepower to beat the 49ers. But the most telling thing is the list of teams the Niners have beaten in 2020: The Jets, Giants, Rams twice, and Patriots. Not exactly the best grouping of teams. In fact, a very flawed list. While the Niners are keeping afloat in a loaded NFC West, the Bills should take this one.