Christian McCaffrey will face his former team for the first time. He leads the San Francisco 49ers into battle when they host the Carolina Panthers at Levi’s Stadium on Monday Night Football. The 49ers are coming off a dominant 41–22 win over the Cardinals at State Farm Stadium. That's where McCaffrey delivered one of his best performances of the season with 121 scrimmage yards and a season-high three touchdowns. San Francisco enters the week with a division-best 4–1 record in NFC West play. That reinforces their status as one of the conference’s elite contenders.
Meanwhile, the Panthers are riding high after a 30–27 overtime victory over the Falcons at Mercedes-Benz Stadium. Bryce Young had an historic 448-yard passing night. That was the most in a single game in franchise history. At 6–5, Carolina remains firmly in the playoff mix as they chase the division-leading Buccaneers. This Week 12 showdown also carries historical weight. Their last meeting came back in Week 5 of 2022. That's when the 49ers rolled to a 37–15 road victory less than two weeks before acquiring McCaffrey.
Panthers vs. 49ers betting odds
Panthers: +7, +100
49ers: -7, -120
Over: 49.5, -108
Under: 49.5, -112
(All odds courtesy of DraftKings)
Panthers vs. 49ers key injuries for Week 12
Panthers: RB Xavier Legette (hip), DT Tershawn Wharton (knee), LB Trevin Wallace (shoulder), LB Christian Rozeboom (hip)
49ers: K Eddy Pineiro (hamstring), LB Luke Gifford (hip), LB Tatum Bethune (ankle), DL Robert Beal (concussion)
Panthers vs. 49ers betting trends
The Panthers and 49ers have played each other seven times from 2010 onwards. The Panthers actually have the upper hand in the head-to-head matchup, 3-4, over those games. The 49ers, however, have won their last two encounters. Those were 37-15 in Week 15 of the 2022 NFL season and 51-13 in Week 8 back in 2019. Entering Week 12, the Panthers just won over the Falcons. Meanwhile, the 49ers are fresh off a victory against the Cardinals.
2025 records:
Carolina, 6-5 straight up, 7-4 ATS; San Francisco, 7-4 straight up, 6-5 ATS
Over/Under
Carolina 6-5; San Francisco, 7-3-1
Keys to Panthers vs. 49ers matchup
Panthers:
Bryce Young’s aerial attack vs. a weakened 49ers secondary
Bryce Young is coming off the best game of his young career. He shredded Atlanta for 448 yards and showed exceptional command of the offense. He now faces a San Francisco secondary ranked 28th in passing yards allowed this season. If Young finds early rhythm, Carolina becomes a legitimate upset threat. That's especially true because of his growing chemistry with Tetairoa McMillan.
Panthers run game vs. 49ers defensive line
Rico Dowdle has been steady all season. He has helped maintain offensive balance. The 49ers’ defensive front, while talented, has had occasional lapses. They currently rank 12th in rushing yards allowed. If Carolina can stay ahead of the chains and control tempo, it will open up deeper shots in the passing game.
Containing the quarterback
Yes, Brock Purdy is not a major rushing threat. That said, he excels when extending plays and throwing on the move. The Panthers must maintain disciplined rush lanes and pressure Purdy without losing containment. Failure to do so could lead to explosive off-script gains.
49ers:
Christian McCaffrey’s revenge game vs. Panthers defense
McCaffrey enters Week 12 as the NFL’s scrimmage-yard leader. He has tallied 1,439 yards from scrimmage and remains the focal point of San Francisco’s offense. Carolina has struggled mightily against receiving backs. They have allowed the third-most RB receptions in the league. Expect Kyle Shanahan to feature McCaffrey heavily in both the run and pass game.
49ers’ motion offense vs. Panthers’ struggle against motion
San Francisco uses motion at the second-highest rate in the NFL. Carolina ranks 30th in defensive efficiency against motion. That appears like a glaring mismatch. The 49ers thrive at isolating defenders and generating yards after the catch. That's an area where Carolina has been vulnerable.
Panthers vs. 49ers prediction and pick
Carolina’s offense has come alive behind Young. They have enough firepower to keep this competitive. However, San Francisco’s motion-based scheme, offensive versatility, and McCaffrey’s all-around dominance present a daunting challenge. The Panthers will move the ball and create scoring opportunities. That said, sustaining drives against the 49ers’ front seven remains difficult.
San Francisco pulls away late, but Carolina does just enough to cover. The offensive momentum of both teams suggests a higher-scoring game.
Final Score Prediction: 49ers 30, Panthers 24 (49ers win, but Panthers cover)
Spread: Panthers +7
Over/Under: Over 49.5
