Best NFL Picks and Predictions Today (How to Bet Panthers vs. 49ers on Monday Night Football in NFL Week 12)

Breaking down the best picks and predictions for the Monday Night Football matchup between the San Francisco 49ers and Carolina Panthers.

San Francisco 49ers running back Christian McCaffrey is a great prop target in Week 12. / Matt Kartozian-Imagn Images

Monday Night Football in Week 12 of the NFL season features two potential playoff teams in the NFC in the Carolina Panthers and San Francisco 49ers.

While many didn’t expect Carolina to be in the mix for a playoff spot this season, Bryce Young’s squad is 6-5 and right in the mix for a wild card spot – or the NFC South crown – in 2025.

Meanwhile, the 49ers are 7-4 despite the fact that Brock Purdy has appeared in just three games this season due to a turf toe injury.

Purdy returned to action for the first time since Week 4 in Week 11, tossing three touchdowns in a win over the Arizona Cardinals.

Oddsmakers are buying the 49ers right now, setting them at seven-point favorites at home in this primetime matchup. It just so happens that the SI Betting team is buying them too, as one of the best bets given out by NFL betting insider Iain MacMillan was for the 49ers to cover in this game.

I’ve decided to share some of our favorite picks and props all in one place, including MacMillan’s breakdown for the 49ers spread bet. 

Here’s a look at the top picks and predictions for Monday Night Football in Week 12. 

Best NFL Picks and Predictions for Panthers vs. 49ers

Odds via DraftKings Sportsbook.

• San Francisco 49ers -7 (-115) vs. Carolina Panthers – Iain MacMillan
• George Kittle Anytime TD (+120) – Peter Dewey
• Tetairoa McMillan Anytime TD (+160) – Peter Dewey
• Christian McCaffrey OVER 42.5 Receiving Yards (-115) – Peter Dewey

San Francisco 49ers -7 (-115) vs. Carolina Panthers – Iain MacMillan

Earlier this week, SI’s NFL betting insider Iain MacMillan shared his favorite bet for this game in his Road to 272 column, and he’s backing San Fran to cover: 

I don't care that the Panthers continue to find ways to win games; I'm going to continue to bet against them. They're 26th in total DVOA, 26th in net yards per play, 26th in EPA per play, and 24th in opponent EPA per play. Meanwhile, they'll face a 49ers team that is starting to get healthy and whose offense looked rejuvenated with Brock Purdy back under center in Week 11 against the Cardinals.

It's time to buy in on the 49ers, and this is an extremely favorable matchup against a Panthers team who is worse than their record indicates. I'll lay the points with San Francisco on Monday Night Football.

George Kittle Anytime TD (+120) – Peter Dewey

George Kittle had arguably his best game of the season with Brock Purdy back in Week 11, and he’s a great bet to build on that on Monday:

There may not be a single player happier to have Brock Purdy back than George Kittle.

The 49ers tight end caught two touchdown passes in Week 11, finishing with six catches for 67 yards on six targets. Now, Kittle thrived under Mac Jones as well – he caught all nine of his targets in Week 10 – but he’s scored three touchdowns in two games with Purdy this season.

Overall, Kittle has five scores in just six games.

I love this matchup for him against a Carolina defense that ranks 29th in the NFL in EPA/Pass and has given up 718 receiving yards and five scores to opposing tight ends in 2025. 

Tetairoa McMillan Anytime TD (+160) – Peter Dewey

Do we have an undervalued Offensive Rookie of the Year candidate in McMillan? He’s made a case the last few weeks, and I’m buying him in this matchup:

Panthers rookie Tetairoa McMillan has really come on as of late, catching two touchdowns in the team's Week 11 win over the Atlanta Falcons.

While McMillan only has four scores in the 2025 season, this is a great matchup for him on Monday night.

San Francisco has allowed the fourth-most passing touchdowns in the NFL (21) through 11 weeks, and it has allowed the second-most passing yards (only the Washington Commanders have given up more).

McMillan is clearly Bryce Young’s favorite option on the outside, as he’s been targeted 89 times in 11 games while registering three games with double-digit looks. He’s a solid bet to score in a game where Carolina (seven-point underdog) is expected to be trailing.

Christian McCaffrey OVER 42.5 Receiving Yards (-115) – Peter Dewey

The Panthers have struggled to defend opposing running backs this season, and CMC could be a major issue for his former team on Monday: 

Christian McCaffrey is going to make an impact across this game, but I’m eyeing his receiving yards against his former team on Monday night.

CMC already has 74 catches for 732 yards and five scores this season, and he’s been targeted a whopping 96 times by Purdy and Mac Jones.

In Purdy’s starts, CMC’s receiving yards have been 73 (10 targets), 92 (11 targets) and 40 (six targets). He’s cleared 42.5 receiving yards in 10 of his 11 games this season, only falling short in Week 11.

Now, he takes on a Carolina defense that has given up the fourth-most receptions (54) to running backs this season. This is a dream matchup – and a very generous line – for the star running back on Monday.

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Odds refresh periodically and are subject to change.

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