Carolina Panthers vs San Francisco 49ers Predictions, Picks & Spread for MNF

• The 49ers are 7-point home favorites over the Panthers on Monday Night Football
• Carolina’s defense ranks 31st in pressure rate this season
• See my Panthers vs 49ers predictions and picks below, plus the latest spread for Monday Night Football

A pair of playoff hopefuls clash on Monday Night Football as the Panthers (6-5, 3-3 away) visit the 49ers (7-4, 2-2 home). Brock Purdy made a successful return to the San Fran lineup last week in a blowout win over Arizona, and online sportsbooks are expecting another convincing victory versus Carolina per the MNF odds.

Kickoff is scheduled for 8:15pm ET / 5:15pm PT from Levi’s Stadium, in Santa Clara, CA, with ESPN providing the broadcast coverage.

Below, you’ll find my Panthers vs 49ers predictions and picks, plus the latest spread for Monday Night Football.

Panthers vs 49ers Predictions and Picks

• San Francisco 49ers -7.0 (-120) at bet365

Neither one of these teams has real upside in the Super Bowl 60 odds, but I think the market is a little light on the Niners in this spot. I’m comfortable laying 7 points in my Panthers vs 49ers picks, as I expect San Fran to be able to do whatever they want on offense.

Let’s start with Purdy. He threw 3 TD in first game back from injury, and should have all the time in the world to carve up a Carolina defense whose pass rush is non-existent. They rank bottom-three in pass rush win rate and EPA/pass, and 31st in pressure rate.

Purdy in a clean pocket is a dangerous proposition, and the numbers bare that out. Last season, Purdy posted an 84.5 passing grade when kept clean, averaging 9.3 yards per attempt, with a 71% completion rate. Under pressure, his completion percentage dropped to 53.6%, while his passing grade plummeted by 30 points.

Carolina Panthers Defensive Stats

Also working in his favor, is the improved health of San Fran’s pass catchers. Both George Kittle and Ricky Pearsall are back from injury, leaving Brandon Aiyuk as the only starting skill position player missing from their roster. Kittle has caught 15 passes and 3 TD in last two games, and now faces a Carolina defense that’s allowed the fifth most production to enemy tight ends.

Sticking with San Fran, this is also a revenge game for Christian McCaffrey. He’ll face his former team for the first time since being traded in 2022, and draws a very favorable matchup. McCaffrey leads the NFL in scrimmage yards, while the Panthers rank bottom-eight in running back production allowed.

On the other side of the ball, Carolina has been a bit of a school yard bully this season. Versus teams outside the playoff picture they’re averaging 23 points per game. Against teams currently projected for the postseason, that number shrinks to 11.25 points per game.

The Niners defense has been decimated by injury in 2025, with the pass rush taking the biggest hit. Without Nick Bosa and Fred Warner they’ve struggled to generate pressure, but that shouldn’t be a big deal against Bryce Young.

The former number one pick has played just as poorly from a clean pocket this season as he has under duress. Young’s passing grade only falls from 65.3 to 60.1 when the heat is on, and he’s actually committed more turnover worthy plays from a clean pocket (6) than he has under pressure (5).

Young is coming off one of the best games of his career, but that was indoors versus the dreadful Falcons. He’s posted passing grades of 37.6 and 51.9 in his last two outdoor games versus playoff worthy competition, with only one big time throw.

CAR Panthers vs SF 49ers Point Spread

Before making any Monday Night Football wager, be sure to consult the best football betting apps. As of Sunday, the best book to bet San Fran -7 is at Bbet365. That wager is available at -120 odds, while the majority of the other commercial books have moved the line to Niners -7.5.

Total-wise, the over/under is painted 49.5 at most online sportsbooks, and that’s a number that six of the Panthers last seven outdoor games have failed to exceed.

Per the NFL public betting percentages, San Fran -7 is attracting the majority of the spread action. That side of the spread is accounting for 62% of the ATS bets, and 54% of the handle.

Odds as of Nov. 23. New customers can claim the FanDuel promo code and get a bonus to bet on MNF.