Week 16 Monday Night Football Betting Preview: 49ers vs Colts
The Indianapolis Colts (8-6) host the San Francisco 49ers (10-4) in a critical Monday Night Football showdown at Lucas Oil Stadium. The 49ers are surging, having won four straight games to cement their status as NFC contenders, while the Colts are clinging to playoff life after dropping four consecutive contests.
With 44-year-old Philip Rivers under center for Indianapolis and the 49ers looking to clinch seeding, this matchup offers intriguing betting angles.
Date: Monday, December 22, 2025, Time: 8:15 PM EST, Venue: Lucas Oil Stadium, Indianapolis, IN
Latest Betting Odds – Spread, Moneyline & Total
| BUSR | 49ers | Colts |
| Spread | -5.5 (-110) | +5.5 (-110) |
| Moneyline | -255 | +200 |
| Total | O 46 | U 46 |
San Francisco 49ers Overview – Form, Trends & Key Factors
Recent Form
They enter Monday night on a four-game winning streak, recently dispatching the Tennessee Titans 37-24 and the Cleveland Browns prior to that. Sitting at 10-4, the San Francisco 49ers have a 96% chance to make the playoffs, which could increase to 100% with a win here or a Detroit Lions loss on Sunday. The offense is humming, ranking 5th in the NFL in EPA per play since Week 10.
ATS Trends
- Overall: 9-5 ATS this season.
- Recent: Covered in 5 of their last 6 games.
- Road Favorites: Historically 4-6 ATS as road favorites of 5 or more points since 2023.
Key Injuries & Impact
- QB Brock Purdy: Healthy and performing well (295+ passing yards in last 3 games vs. AFC South).
- RB Christian McCaffrey: Listed as DNP (rest) early in the week but expected to play. His presence is vital; the offense averages over 30 points when he is fully utilized.
- Defense: DE Yetur Gross-Matos (Hamstring) and CB Renardo Green (Neck) are limited.
Strengths & Weaknesses
- Strength: Offensive Efficiency. Brock Purdy and the passing attack rank 2nd in success rate since Week 10.
- Weakness: Run Defense. Surprisingly, the 49ers rank dead last in rushing success rate allowed since Week 10, a vulnerability Jonathan Taylor will look to exploit.
Indianapolis Colts Overview – Form, Trends & Key Factors
Recent Form
The Colts are in freefall, losing four straight games to drop to 8-6. Their playoff probability has cratered to 13.7%, making this a virtual must-win. Last week, they nearly upset the Seahawks with Philip Rivers at QB, losing 18-16 on a last-second field goal.
ATS Trends
- Home: 6-1 SU and 4-3 ATS at Lucas Oil Stadium.
- Underdog: 4-1 ATS as an underdog this season (two outright wins).
- Vs. SF: The Colts are 3-0 ATS in their last three meetings against the 49ers.
Key Injuries & Impact
- QB Situation: With Anthony Richardson (Orbital) and Daniel Jones (Achilles) out, Philip Rivers makes his second start. He threw for 120 yards and 1 TD last week.
- Defense: LB Germaine Pratt (Personal) and CB Sauce Gardner (Calf) were DNP mid-week, significantly weakening the coverage unit.
Strengths & Weaknesses
- Strength: The Run Game. The Colts average 128.5 rushing yards per game (6th in the NFL). Jonathan Taylor leads the league with 1,443 rushing yards and 18 touchdowns.
- Weakness: Passing Explosiveness. With an aging Rivers, the Colts lack the ability to stretch the field, relying heavily on check-downs and the run game.
Head-to-Head History
The Colts have dominated this matchup historically, owning a 27-19 all-time record.
- Streak: Indianapolis has won the last five meetings.
- Last Meeting: Colts won 30-18 in 2021.
- Notable Trend: The Colts are 3-0 ATS in the last three games against San Francisco.
Matchup Breakdown – Offense vs. Defense
When the 49ers Have the Ball
- Elite Efficiency: The offense is humming, facing a Colts unit that recently surrendered 36 points to Jacksonville and 27 to Pittsburgh.
- Attacking the Seam: Brock Purdy has been lethal against the AFC South, consistently feeding George Kittle (67+ receiving yards in five straight games) in the middle of the field.
- YAC Potential: Deebo Samuel and Jauan Jennings are primed to exploit a secondary missing key starters like Sauce Gardner.
- Fast Starters: San Francisco looks to score early, currently holding the longest active streak in the league for winning the first quarter (4 games).
When the Colts Have the Ball
- Run-First Identity: The clear game plan is feeding Jonathan Taylor (121+ scrimmage yards in last three home games) to attack a 49ers run defense that has regressed significantly over the last month.
- Game Management: Expect Philip Rivers to rely on short, high-percentage throws to keep the clock moving and minimize turnovers.
- Reliable Targets: Michael Pittman Jr. serves as the primary safety valve for Rivers in the short passing game.
- Red Zone Consistency: Taylor remains the engine of the offense, having scored a touchdown in 11 of his last 12 appearances as a betting favorite.
Over/Under Analysis & Betting Trends
The Total is set at 46.5.
- San Francisco: 8 of their 14 games have gone OVER the total.
- Indianapolis: 7 of 14 games have hit the OVER.
- Pace: The 49ers are efficient but deliberate. The Colts, with Rivers, will likely try to slow the game down to keep Purdy off the field.
- Trend: The total has gone UNDER in four of the Colts’ last six games, reflecting their offensive struggles without a mobile QB. However, the 49ers have scored 30+ regularly.
Lean: The Under 46.5 looks appealing given Rivers’ limitations and the Colts’ likely strategy to grind the clock with Taylor.
Best Prop Bets
- Jonathan Taylor Over 83.5 Rushing Yards: The 49ers rank 29th in defensive success rate since Week 10 and dead last against the run. Taylor has recorded 83+ rushing yards in his four previous December appearances at Lucas Oil Stadium. He is the entire offense right now.
- George Kittle Over 54.5 Receiving Yards: Kittle has recorded 67+ receiving yards in each of his last five games. The Colts’ linebackers will be preoccupied with stopping McCaffrey, leaving the seam open for Kittle.
- Brock Purdy Over 11.5 Rushing Yards: Purdy has recorded 11+ rushing yards in 19 of his last 22 appearances as a favorite. He is opportunistic with his legs, especially on third downs.
Prediction & Best Bet
Pick: Indianapolis Colts +5.5
While the San Francisco 49ers are the superior team and should win this game outright, the betting value lies with the home underdog. The Colts are fighting for their playoff lives, and teams in “must-win” spots at home often perform above expectations.
The stylistic matchup favors a close game. The 49ers’ recent inability to stop the run aligns perfectly with the Colts’ greatest strength: Jonathan Taylor. If Indianapolis can churn out 4-5 yard carries and control the clock, they can shorten the game and keep the score within the spread. The Colts are 4-1 ATS as underdogs this year, and Lucas Oil Stadium is a difficult place to play on Monday Night.
Expect the 49ers to win a tight one, perhaps 24-20, allowing the Colts to cover the number.
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