49ers vs. Panthers prediction, odds: ‘Monday Night Football’ picks from proven model

The teams hoping to finally end their winning streak will meet on Monday Night Football, where San Francisco 49ers accept Carolina Panthers. San Francisco (7-4) has alternated wins and losses in its last nine games and is coming off a 41-22 win over Arizona in Week 11. Carolina (6-5) has alternated wins and losses in its last five games, most recently beating Atlanta 30-27 in overtime on Sunday. The Niners entered Week 12 of the NFL ranked seventh in the NFC standings, while the Panthers were ranked ninth. Linebackers Christian Roseboom (hip/hamstring) and Trevin Wallace (shoulder), along with center Cade Mays (ankle), are out for Carolina. Kicker Eddie Pineiro (hamstring) and linebacker Tatum Bethune (ankle) are out for the Niners.

Kickoff will take place at 8:15 pm ET at Levi's Stadium in Santa Clara, California. The Niners have won their last two matches, with the last meeting coming in 2022. San Francisco is a 7.5-point favorite in the latest Panthers vs. 49ers odds, and the over/under for total points scored is 49.5. Before making any picks between the 49ers and Panthers, be sure to see what SportsLine's projection model says.

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The model, which simulates every NFL game 10,000 times, costs more than $7,000 for $100 top players. NFL Pick since its creation. The model enters Week 12 with a 48-33 record in the top-rated samples going back to 2024. NFL Betting poking around in bookmakers and further betting sites could see strong profits.

The model is now focused on Carolina vs San Francisco. You can head over to SportsLine now to see his picks. Here are a few NFL odds and betting lines for the 49ers vs. Panthers game:

Why the Panthers might cover

Bryce Young has been one of the best quarterbacks this season, going 7-2 in his last nine starts. Carolina has played in five of six games against NFC opponents in 2025, and its MNF opponent has major holes on defense. The Niners can't get to the quarterback or get the ball, as they rank last in defensive sacks and also have the second-most picks. That should give Young some comfort in the pocket while he also has the No. 4 hitter in the league. Rico Dowdle lean. Finally, the 49ers, who have eight takeaways compared to just one takeaway at Levi's Stadium this year, don't seem to have much of a home-field advantage. Find out which team to support at SportsLine.

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Why the 49ers might be covering.

Finally healthy Brock Purdy showed what San Francisco is capable of last week as the Niners scored a season-high 41 points after averaging just 22 for the season. The offense, however, is running through Christian McCaffreywho leads the NFL in rushing yards and is on pace for 1,000 yard seasons both on the ground and in the air. George Kittle has also made an impact since coming off IR, scoring four goals in his last four games, and Sun won't see the worst offense on Monday. Carolina ranks 28th in scoring with an additional 10 ranking in passing attack, third in scoring and yards per game. Find out which team to support at SportsLine.

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How to choose between 49ers vs. Panthers

For the Panthers vs. 49ers on Monday Night Football, the model is leaning toward the total, projecting 52 points. It also says one side of the spread hits more than 50% of the time on A-rated picks. See what it's all about at SportsLine, and use promo code CHAMPIONSHIP to get your first month of SportsLine for $1.

Who will win 49ers vs. Panthers and which side of the spread lands in more than 50% of simulations with A-ranked picks? Visit SportsLine now to find out which side of the Panthers vs. lineup. The 49ers need to jump, all from a 48-33 model on the highest-rated picks from 2024.and find out.