San Francisco 49ers vs. Indianapolis Colts: Experts release early Week 16 preview [2025]

The San Francisco 49ers and Indianapolis Colts will meet in Week 16 of the NFL season at Lucas Oil Stadium on Monday, December 22, 2025, starting at 8:15PM ET.

Initial simulations from Dimers' trusted NFL model favor the 49ers as the most likely winner of this cross-conference clash.

For updates all week long, including best bets, player prop projections and touchdown probabilities, check out our interactive 49ers vs. Colts predictions page.

San Francisco vs. Indianapolis early predictions

Leveraging trusted machine learning and analysis, we have simulated the Niners vs. Colts game 10,000 times as part of our NFL predictions coverage. Here are the latest insights:

• Straight up win probabilities: 49ers 69%, Colts 31%
• Predicted final score: 49ers 25-20 Colts
• Spread: 49ers (-6.5) 43%, Colts (+6.5) 57%
• Total points (45.5): Over 53%, Under 47%

As of December 15, 2025, these 49ers-Colts calculations and predictions reflect the latest data and insights available.

Niners vs. Colts Week 16 details

The NFL Week 16 matchup between the Colts and 49ers at Lucas Oil Stadium is scheduled for December 22, 2025.

• Who: San Francisco 49ers vs. Indianapolis Colts
• Date: Monday, December 22, 2025
• Time: 8:15PM ET/5:15PM PT
• Venue: Lucas Oil Stadium

Niners vs. Colts opening odds

We've researched the best betting odds across America for this Week 16 game, which are listed here:

• Spread: 49ers -6.5 (-110), Colts +6.5 (-110)
• Moneyline: 49ers -270, Colts +260
• Total: Over/Under 45.5 (-110/-110)

Odds may continue to move—track live changes via our NFL odds page.

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Conclusion

We predict the 49ers, with a 69% win probability, will likely beat the Colts in Week 16 of the NFL season. Dimers.com will provide full game coverage closer to kickoff, so stay tuned for updates.

Enhanced by AI and automation, this article delivers quick, accurate insights on the 49ers vs. Colts game, with human oversight maintaining high editorial quality. Our predictions are sourced from up-to-date data to help you make informed decisions. For additional resources and advice on responsible gambling, please call 1-800-GAMBLER.

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