49ers vs. Panthers prediction, odds: 'Monday Night Football' picks, best bets from proven model

Two teams hoping to finally put together a winning streak will meet on 'Monday Night Football' as the San Francisco 49ers host the Carolina Panthers. San Fran (7-4) has alternated wins and losses over its last nine games and is coming off a 41-22 victory over Arizona in Week 11. Carolina (6-5) has alternated wins and losses over its last five contests, most recently knocking off Atlanta, 30-27 in overtime, on Sunday. The Niners entered NFL Week 12 ranked seventh in the NFC standings, with the Panthers ninth.

Kickoff is at 8:15 p.m. ET from Levi's Stadium in Santa Clara, Calif. The Niners have won the last two matchups, with the most recent meeting coming in 2022. San Francisco is the 7.5-point favorite in the latest Panthers vs. 49ers odds, while the over/under for total points scored is 49.5. Before making any 49ers vs. Panthers picks, be sure to see what the SportsLine projection model has to say. 

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The model, which simulates every NFL game 10,000 times, is up well over $7,000 for $100 players on top-rated NFL picks since its inception. The model enters Week 12 on a 48-33 run on top-rated picks dating back to 2024. Anybody following its NFL betting picks at sportsbooks and on betting sites could have seen strong returns.  

Now, the model has zeroed in on Carolina vs. San Francisco. You can head to SportsLine now to see its picks. Here are several NFL odds and betting lines for 49ers vs. Panthers:

Why the Panthers can cover

Bryce Young has been one of the best quarterbacks versus the spread this season, going 7-2 ATS over his last nine starts. Carolina has covered in five of six games versus NFC opponents in 2025, and its MNF opponent has major defensive holes. The Niners can neither get to the quarterback nor take the ball away as they rank dead last in defensive sacks and also have the second-fewest picks. That should bring comfort to Young in the pocket, while he also has the league's No. 4 rusher in Rico Dowdle to lean on. Finally, there doesn't appear to be much of a home-field advantage for the 49ers who have eight giveaways versus just one takeaway at Levi's Stadium this year. See which team to back at SportsLine.

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Why the 49ers can cover

A finally healthy Brock Purdy showed what San Francisco is capable of last week as the Niners scored a season-high of 41 points after averaging just 22 on the season. The offense, however, runs through Christian McCaffrey, who leads the NFL in scrimmage yards and is on pace for 1,000-yard seasons both on the ground and through the air. George Kittle has also made an impact since coming off IR, with four scores over his last four games, and San won't see the most threatening of offenses come Monday. Carolina ranks 28th in scoring, with additional bottom-10 marks in passing offense, third down offense and yards per play. See which team to back at SportsLine. 

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How to make 49ers vs. Panthers picks

For Panthers vs. 49ers on 'Monday Night Football,' the model is leaning Over the total, projecting 52 combined points. It also says one side of the spread hits well over 50% of the time in an A-rated pick. See what it is at SportsLine, and use promo code CHAMPIONSHIP to get your first month at SportsLine for $1.

Who wins 49ers vs. Panthers, and which side of the spread hits in well over 50% of simulations in an A-rated pick? Visit SportsLine now to see which side of the Panthers vs. 49ers spread you need to jump, all from the model that is 48-33 on top-rated picks since 2024, and find out.