Panthers vs 49ers NFL Week 12 MNF Best Picks

Week 12 of the 2025 NFL season will conclude with a Monday Night Football matchup between two playoff hopefuls in the NFC. The action kicks off at 8:15 PM ET on ESPN with the San Francisco 49ers playing host to the Carolina Panthers. The 49ers need to keep winning to keep pace in the NFC playoff picture, while the Panthers enter this one in a tie for first in the NFC South with the Buccaneers. Which team will come out on top at Levi's Stadium? Let’s get into our Panthers vs 49ers best bets for MNF.

Panthers vs 49ers predictions

• Pick #1: Carolina Panthers +7.5 over San Francisco 49ers (-112)
• Pick #2: Over 49.5 (-110)
• Pick #3: George Kittle anytime touchdown scorer (+145)

PICK #1: Panthers +7.5 over 49ers (-112)

This is a game that is a lot more compelling than most would’ve thought prior to the season, and we are interested in the visitors to keep things close on Monday. Carolina has been a pleasant surprise team in the NFL this season, and backing Bryce Young and company on the road is certainly worth a shot in a game where the Carolina offense should hold some advantages over the opposing defense. 

The San Francisco defense has been struggling mightily in recent weeks as they deal with injuries. Currently, the 49ers sit at 26th in EPA per play and 31st in success rate allowed on the season, and there’s no reason to expect that this changes anytime soon. On the other side, Carolina has been an excellent rushing team since the insertion of Rico Dowdle into the lineup, so the Panthers should be able to stay ahead of the chains and put themselves in favorable down and distances against this vulnerable 49ers defense. With that in mind, it’s hard to ignore getting more than a touchdown with the Panthers in this one. 

PICK #2: Over 49.5 (-110)

Given the fact that this line is currently sitting under the key number of 51, our lean for the game total is on the over. While the San Francisco offense is not a unit that operates at an extremely fast pace, the 49ers should have a pretty favorable matchup at hand against a Panthers defense that has been one of the lesser defenses in football — with Carolina currently sitting at 24th in opponent adjusted EPA per play and 28th in EPA per pass. 

On the other side, we know that San Francisco’s defense has been taking on water in recent weeks and Bryce Young is coming off an excellent game (450 passing yards, three touchdowns) against a Falcons defensive front that has plenty of juice and has caused problems for plenty of quarterbacks this season. Look for another high-scoring game for both of these sides on Monday. 

PICK #3: George Kittle anytime touchdown scorer (+145)

For our best player prop bet for MNF, let’s target George Kittle to haul in a touchdown for the third straight game. Few teams are worse at defending the tight end position than this Panthers defense, and they have actually allowed more than half of their opponents’ receiving yards to come via TE this season. After a fairly easy matchup last week, the Panthers will now have to deal with Kittle, who is in the midst of a very solid season to lead this 49ers pass-catching group. The veteran tight end has recorded five touchdowns over his last six games played, so let’s back the big man to find his way into the end zone once again on Monday Night Football.