49ers vs Colts Prediction, Odds & Best Prop Bets – NFL, Week 16

BetMGM Betting Dec 19, 2025, 6:00 PM

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A general overall interior view of Lucas Oil Stadium as Chicago Bears take on the Indianapolis Colts during an NFL football game, Sunday, Sept. 22, 2024, in Indianapolis. The Colts defeated the Bears 21-16. (AP Photo/Zach Bolinger)

(AP Photo/Zach Bolinger)

The Favorite Team are Favorite Spread point favorites vs the Underdog Team
Total (Over/Under): 46.5 points
Watch this game on ABC | ESPN | ESPD

The San Francisco 49ers (10-4-0) visit Lucas Oil Stadium to take on the Indianapolis Colts (8-6-0) on Dec. 22. Kickoff is scheduled for 8:15pm EST in Indianapolis, IN.

The are betting favorites in this matchup, with the spread sitting at ().

The 49ers vs. Colts Over/Under is 46.5 total points for the game.

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49ers vs. Colts Odds, Spread, Over/Under

49ers vs. Colts Prediction

The winning team model predicts the 49ers will win this game with 70.2% confidence, based on game simulations, player injuries, offensive & defensive matchups and recent game results.

49ers vs Colts Spread Prediction

Based on recent against-the-spread trends, the model predicts the 49ers will cover the spread with 59.2% confidence.

This prediction against the spread factors in ATS performances for both teams, opening and current betting lines plus public and sharp money already wagered on this matchup.

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We’ve highlighted some favorite NFL player prop bets for 49ers players this game, looking at profitable historical betting trends:

Best 49ers Player Prop Bets Today

Christian McCaffrey has hit the Longest Rush Under in 11 of his last 14 games (+7.60 Units / 46% ROI)
Brian Robinson has hit the Receiving Yards Under in 9 of his last 11 games (+6.80 Units / 52% ROI)
Christian McCaffrey has hit the Receiving Yards Over in 10 of his last 14 games (+5.35 Units / 33% ROI)
Brian Robinson has hit the Receptions Under in 8 of his last 11 games (+5.10 Units / 37% ROI)
George Kittle has hit the Longest Reception Over in his last 5 games (+5.00 Units / 88% ROI)

And here are some top NFL player prop bets for Colts players for this matchup, looking at profitable historical betting trends:

Best Colts Player Prop Best Bets Today

Alec Pierce has hit the Receiving Yards Over in 12 of his last 14 games (+9.70 Units / 60% ROI)
Alec Pierce has hit the Longest Reception Over in 10 of his last 12 games (+7.75 Units / 56% ROI)
Tyler Warren has hit the Receptions Under in 9 of his last 13 games (+5.10 Units / 33% ROI)
Jonathan Taylor has hit the Longest Reception Over in 6 of his last 7 games at home (+4.90 Units / 61% ROI)
Tyler Warren has hit the Receiving Yards Under in 6 of his last 7 games (+4.85 Units / 61% ROI)

49ers Best Bets:

The San Francisco 49ers have hit the 1H Game Total Over in 14 of their last 20 games (+9.35 Units / 40% ROI)
The San Francisco 49ers have hit the Game Total Over in 14 of their last 20 games (+8.50 Units / 39% ROI)
The San Francisco 49ers have hit the 3Q Game Total Over in 13 of their last 17 games (+8.15 Units / 38% ROI)
The San Francisco 49ers have covered the 1Q Spread in 14 of their last 20 games (+6.95 Units / 28% ROI)
The San Francisco 49ers have hit the Moneyline in 12 of their last 20 games (+6.85 Units / 20% ROI)

Colts Best Bets:

The Indianapolis Colts have hit the 2Q Game Total Over in 12 of their last 17 games (+6.45 Units / 32% ROI)
The Indianapolis Colts have hit the Team Total Over in 8 of their last 10 games at home (+5.80 Units / 51% ROI)
The Indianapolis Colts have hit the 1H Team Total Over in 13 of their last 20 games (+5.80 Units / 23% ROI)
The Indianapolis Colts have hit the Game Total Over in 13 of their last 20 games (+5.30 Units / 24% ROI)
The Indianapolis Colts have hit the 4Q Game Total Over in 11 of their last 17 games (+5.20 Units / 27% ROI)

49ers Against the Spread (ATS) Record

Against the spread this NFL season, the 49ers are 9-5 (+3.5 Units / 22.73% ROI).

49ers are 10-4 when betting on the Moneyline for +7.95 Units / 28.49% ROI
49ers are 8-5 when betting the Over for +2.5 Units / 16.23% ROI
49ers are 5-8 when betting the Under for -3.8 Units / ROI

Colts Against the Spread (ATS) Record

Against the spread this NFL season, the Colts are 8-6 (+1.4 Units / 9.09% ROI).

Colts are 8-6 when betting on the Moneyline for +0.55 Units / 1.54% ROI
Colts are 7-7 when betting the Over for -0.7 Units / -4.55% ROI
Colts are 7-7 when betting the Under for -0.7 Units / -4.55% ROI

San Francisco 49ers: Keys to the Game vs. the Indianapolis Colts

The Colts ran successful plays on 9% of pass attempts in the 2nd half in Week 15 — worst in NFL; League Avg: 48%.

The Colts have averaged 0.19 epa per play at home this season — best in NFL; League Avg: 0.02.

The Colts have scored on 54% of their drives (35/65) in the 2nd half this season — best in NFL; League Avg: 37%.

The Colts ran successful plays on 23% of plays in the 2nd half in Week 15 — 3rd-worst in NFL; League Avg: 44%.

Indianapolis Colts: Keys to the Game vs. the San Francisco 49ers

The 49ers have faced a blitz just 8% of the time this season — lowest in NFL; League Avg: 14%.

The 49ers have run successful plays on 63% of pass attempts in the 3rd quarter this season — best in NFL; League Avg: 49%.

The 49ers have run 61% of their plays in their opponent’s territory in the 2nd half this season — best in NFL; League Avg: 49%.

The 49ers have run successful plays on 60% of plays on first read passes this season — best in NFL; League Avg: 52%.

Additional Matchup Notes for San Francisco 49ers vs. Indianapolis Colts