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49ers vs. Colts prediction: Why San Francisco is favored to win ‘MNF’ Week 16 [2025]
Updated: | First published:
Written by Dave Garofolo, Content Producer
Get San Francisco 49ers vs Indianapolis Colts predictions for NFL Monday.
The Indianapolis Colts will square off with the favored San Francisco 49ers in NFL Week 16 action at Lucas Oil Stadium on Monday, starting at 8:15 PM ET.
Based on the latest simulations, Dimers' proven NFL model projects the 49ers as the most likely winner of the 49ers vs. Colts game.
This article offers further insights into Monday's matchup, including projected touchdown scorers, best bets and player prop picks.
Niners vs. Colts prediction: Who will win ‘Monday Night Football’?
Since our 49ers-Colts predictions earlier in the week, we have simulated the outcome of Monday's NFL game between the 49ers and Colts 10,000 times as part of our NFL predictions coverage.
Our independent predictive model currently gives the 49ers a 64% chance of defeating the Colts in Week 16 of the NFL season. Our predicted final score has the 49ers winning 25-21.
According to our model, the Colts (+4.5) have a 54% chance of covering the spread, while the 46.5-point over/under has an equal 50-50 chance of hitting.
To see win probabilities for every matchup this week, check out our expert NFL Week 16 straight up picks.
49ers vs. Colts odds
We have researched the best NFL odds in America for this game, which are listed here:
| Bet Type | 49ers | Colts |
|---|---|---|
| Spread | -4.5 (-105) | +4.5 (-112) |
| Moneyline | -220 | +185 |
| Total | o46.5 (-102) | u46.5 (-110) |
All odds are correct at the time of publication and are subject to change.
49ers vs. Colts picks and best bet
After matching our predictions against the best current odds, we can reveal our picks for each of the major markets. Plus, find our best bet for the game below:
| Bet Type | Pick | Bet Now |
|---|---|---|
| Spread | Colts +4.5 | -112 |
| Moneyline | Colts | +185 |
| Total | Over 46.5 | -102 |
According to our NFL best bets, the top play to make on this game is Colts +4.5 at the spread.
49ers vs. Colts TD scorers
Who will score a touchdown in 49ers vs. Colts?
According to our list of touchdown scorer predictions for MNF, Jonathan Taylor is most likely to score an anytime TD in 49ers vs. Colts.
Our projections give Taylor a 65.9% chance of scoring a TD at Lucas Oil Stadium, while the running back is an 18.3% chance of scoring the first touchdown the game.
Anytime touchdown scorer predictions
San Francisco 49ers
| Player | Anytime TD Probability |
|---|---|
| Christian McCaffrey (RB) | 63.0% |
| George Kittle (TE) | 40.5% |
| Jauan Jennings (WR) | 37.7% |
| Brian Robinson (RB) | 19.1% |
| Brock Purdy (QB) | 16.6% |
Indianapolis Colts
| Player | Anytime TD Probability |
|---|---|
| Jonathan Taylor (RB) | 65.9% |
| Tyler Warren (TE) | 27.9% |
| Michael Pittman (WR) | 22.3% |
| Josh Downs (WR) | 22.1% |
| Alec Pierce (WR) | 18.5% |
First touchdown scorer predictions
San Francisco 49ers
| Player | First TD Probability |
|---|---|
| Christian McCaffrey (RB) | 17.5% |
| George Kittle (TE) | 9.2% |
| Jauan Jennings (WR) | 8.3% |
| Brian Robinson (RB) | 3.7% |
| Brock Purdy (QB) | 3.2% |
Indianapolis Colts
| Player | First TD Probability |
|---|---|
| Jonathan Taylor (RB) | 18.3% |
| Tyler Warren (TE) | 5.6% |
| Michael Pittman (WR) | 4.3% |
| Josh Downs (WR) | 4.3% |
| Alec Pierce (WR) | 3.5% |
49ers vs Colts player props
Discover our predictions for the players likely to lead in passing, rushing and receiving yards for both the 49ers and Colts. Head to our NFL player projections page now to access a full list of player prop projections for every offensive player in this matchup and all other Week 16 games.
Quarterbacks
Of the starting quarterbacks, the 49ers' Brock Purdy is projected for 249 passing yards. The Colts' Philip Rivers is expected to throw for just 182 yards.
| Player | Proj. Pass Yards |
|---|---|
| Brock Purdy (SF) | 249 |
| Philip Rivers (IND) | 182 |
49ers rushing
| Player | Proj. Rush Yards |
|---|---|
| Christian McCaffrey | 66 |
| Brian Robinson | 24 |
| Brock Purdy | 16 |
Colts rushing
| Player | Proj. Rush Yards |
|---|---|
| Jonathan Taylor | 105 |
| Ameer Abdullah | 14 |
| Tyler Goodson | 4 |
49ers receiving
| Player | Proj. Rec. Yards |
|---|---|
| George Kittle | 66 |
| Jauan Jennings | 60 |
| Christian McCaffrey | 42 |
| Kendrick Bourne | 31 |
| Demarcus Robinson | 24 |
Colts receiving
| Player | Proj. Rec. Yards |
|---|---|
| Tyler Warren | 40 |
| Michael Pittman | 39 |
| Josh Downs | 33 |
| Alec Pierce | 27 |
| Jonathan Taylor | 22 |
Niners vs. Colts game-day updates and essential details
The NFL Week 16 game between the Colts and 49ers at Lucas Oil Stadium is scheduled to begin at 8:15 PM ET.
- Who: San Francisco 49ers vs. Indianapolis Colts
- Date: Monday, December 22, 2025
- Time: 8:15 PM ET/5:15PM PT
- Venue: Lucas Oil Stadium
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Conclusion
We predict the 49ers, with a 64% win probability, will likely beat the Colts in Week 16 of the NFL season.
AI and automation have enhanced this article to quickly deliver accurate 49ers vs. Colts insights, with human oversight ensuring 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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Dave Garofolo uses sophisticated AI-driven analytics to make predictions and evaluate player performances in the NBA, MLB, NFL, NHL, NCAAM, and PGA TOUR tournaments, crafting insightful game and prop previews.
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