A late-December cross-conference matchup brings the 49ers’ playoff-tested machine into Indianapolis to face a Colts team fighting for AFC positioning. This game has the feel of a measuring stick for Indy and a business trip for San Francisco — the kind of matchup that often comes down to execution, discipline, and mistakes. With the San Francisco listed as 5.5-point road favorites and the total sitting at 46, what’s the best bet in this 49ers vs. Colts clash?
49ers vs. Colts Game Day Information
- 📅 Date: Monday, December 22, 2025
- ⏰ Kickoff: 8:15 p.m. ET
- 📍 Stadium: Lucas Oil Stadium, Indianapolis, IN
- 📺 TV: ESPN
Opening line: 49ers -3 / Colts +3
Key Notes & Storylines
49ers momentum & playoff seeding: San Francisco recently clinched a playoff berth and sits at 10-4, with wins in their last stretch that have them vying for top NFC seeding.
Colts urgency & struggles: Indianapolis enters 8-6 and fighting for AFC relevance. However, they’ve dropped multiple games and hope home field and veteran leadership can flip the narrative.
Veteran QB storylines: The Colts’ unexpected pivot to Philip Rivers — coming out of retirement — adds intrigue under center as Rivers seeks to guide Indy’s offense.
Divisional ramifications: With postseason stakes looming in both conferences, this clash isn’t just about records but tiebreakers and momentum heading into the final weeks.
Public Betting Tickets
Numbers update frequently — check the latest on the NFL public betting chart and learn usage basics in our public betting guide.
Injury Reports
49ers Injuries
Out:
-
Ricky Pearsall, WR – Knee/ankle (out)
-
Renardo Green, CB – Neck (out)
-
Kurtis Rourke, QB – (out)
Questionable/Active:
-
Yetur Gross-Matos, DE – Hamstring (questionable)
-
Tatum Bethune, LB & Sam Okuayinonu, DE – Expected back
-
Eric Kendricks, LB – Expected active
Colts Injuries
Out:
-
Anthony Richardson, QB – (eye/orbital fracture)
-
Sauce Gardner, CB – Calf
-
Daniel Scott, S – (out)
Questionable: -
DeForest Buckner, DT – Neck
-
Bernhard Raimann, LT – Elbow
The 49ers have dealt with their share of key absences but appear healthier at multiple spots, while the Colts are still navigating major losses on both sides of the ball.
49ers vs. Colts MNF Picks & Predictions
This matchup feels like a road test for the red-hot 49ers against a resilient Colts squad that’s struggled for offensive consistency. San Francisco’s balanced attack and playoff momentum should carry them past Indianapolis, though expect a competitive, moderately scoring game in Lucas Oil’s dome environment.
Prediction: 49ers win 27-20 (take San Francisco -5.5)
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