San Francisco 49ers vs Indianapolis Colts Picks and Prediction for Monday December 22 2025

By: Eddie Kline Published 12/15/2025, 08:43 PM ET

49ers Preview

Lucas Oil Stadium will play host to a Monday night NFL clash between the San Francisco 49ers and the Indianapolis Colts. Get ready for all the football action with our NFL Picks. The 49ers (10-4) have reeled off four straight victories and are just a game out of first place in the NFC West Division. On Sunday, San Francisco outscored Tennessee by 14 points in the third quarter to pull away for a 37-24 home victory.

San Francisco QB Brock Purdy completed 23 of 30 passes for 295 yards and three touchdowns. All-Pro RB Christian McCaffrey carried 22 times for 72 yards and a score. Ricky Pearsall added a game-high 96 receiving yards for the 49ers, who outgained the Titans by a 430-306 margin.

Colts Preview

The Indianapolis Colts are looking to snap a four-game losing streak and have lost QB Daniel Jones to a torn Achilles. The Colts (8-6) rank eighth in the league in total offense and are averaging 28 points per contest. On Sunday, Indianapolis managed just 215 total yards and committed a turnover during an 18-16 road loss against Seattle.

K Blake Grupe booted a 60-yard field goal with less than a minute remaining to give Indianapolis a 16-15 lead. 44-year old QB Philip Rivers (120 pass yds) made his first start in nearly five years and threw an eight-yard touchdown to Josh Downs. All-Pro RB Jonathan Taylor added 87 rushing yards in a losing effort for the Colts.

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49ers vs Colts Pick

Indianapolis CB Sauce Gardner (calf) did not play during Sunday’s loss and his status for this game is uncertain. The 49ers rank in the middle of the pack defensively and the Colts will be able to get their ground game going. San Francisco will extend their winning streak to five, but Indianapolis will cover at home. Final Score Prediction, San Francisco 49ers win 24-23. The best sportsbooks are the best way to go when you are betting on the 49ers. Make sure you know about how the fans are looking on prediction markets for the Colts with the Onyx Odds promo code. Getting the most out of your bets on Colts vs 49ers can be done by using the Fanatics Sportsbook promo code.

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