49ers vs. Colts 2025 Prediction, Odds, Picks - Dec 22

The San Francisco 49ers (10-4) are the favorites, expected to win by at least a field goal but less than a touchdown (currently -5.5) over the Indianapolis Colts (8-6). The 49ers have taken four games straight. The expected point total for the matchup is 46.5.

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49ers vs. Colts Odds & Betting Lines

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49ers vs. Colts Prediction & Pick

• Pick ATS: Colts (+5.5)
  
• Pick OU: Over (46.5)
  
• Prediction: Colts 24 - 49ers 23

How to Watch San Francisco vs. Indianapolis

• Game date: Monday, December 22, 2025
• Time: 8:15 p.m. ET
• Venue: Lucas Oil Stadium
• Location: Indianapolis, Indiana
• TV: ESPN
• Streaming: FOX One + ESPN Bundle

49ers vs. Colts Recent Matchups

• Indianapolis has a 2-0 record against San Francisco in their last two matchups.
• Over their last two head-to-head matchups, Indianapolis has scored 56 points, while San Francisco has accumulated 41.

San Francisco Betting Info

• San Francisco has played 14 games, posting nine wins against the spread.
• The 49ers have been favored by 5.5 points or more three times this season, and covered the spread in each of them.
• San Francisco contests this year have gone over the point total 57.1% of the time (eight times in 14 games with a set point total).
• The 49ers have put together a 9-1 record in games they played as the moneyline favorite (winning 90% of those games).
• The 49ers have a 71.4% chance to win this game, based on the implied probability of the moneyline.

49ers Stats

San Francisco's Key Players

Offense

• Christian McCaffrey has recorded 922 rushing yards with nine touchdowns (65.9 yards per game through 14 games). His 3.6 yards per attempt rank 43rd in the league.
• McCaffrey has been targeted 108 times in the receiving game and has 86 catches (6.1 per game) for 820 yards (58.6 per game) and five TDs.
• Mac Jones has 2,151 passing yards, 13 touchdowns and six interceptions this year. He has completed 69.6% of his attempts, averaging 215.1 yards per game and 7.4 per attempt.
• Brock Purdy has 1,442 passing yards in six games this year, averaging 240.3 per game with a 67.9% completion percentage and 12 touchdowns against seven interceptions.
• He has also rushed for 87 yards (third on the 49ers) and added one touchdown on the ground, averaging 14.5 yards per game.
• Jauan Jennings averages 3.7 receptions and 41.3 yards per game, and has 495 total receiving yards and 44 catches. He's gotten 74 total targets, and has caught seven touchdown passes (ninth in the NFL).

Defense

• Over on defense, Dee Winters has 89 tackles and 7.0 TFL in 2025.
• Upton Stout has 66 tackles, 4.0 TFL, and one sack this season. He's second on the 49ers in tackles.
• Bryce Huff has put up 25 tackles, 6.0 TFL, and four sacks this year.
• So far this season, Ji'Ayir Brown has 45 tackles, 1.0 TFL, and two interceptions.

Indianapolis Betting Info

• Indianapolis has covered the spread in a game eight times this year (8-6-0).
• The Colts have been underdogs by 5.5 points or more once this season and covered the spread.
• Indianapolis games have gone over the total seven times this year.
• The Colts have entered the game as underdogs five times this season and won twice.
• Oddsmakers have implied with the moneyline set for this matchup that the Colts have a 32.8% chance to win.

Colts Stats

Indianapolis' Key Players

Offense

• Jonathan Taylor has rushed for 16 touchdowns this year, and has put up 1,443 total rushing yards (103.1 per game and 5.3 per carry).
• Taylor's contributions include 38 receptions (2.7 per game) on 44 targets for 318 yards (22.7 per game) and two receiving touchdowns.
• Michael Pittman Jr. has 72 catches for 725 yards and seven receiving touchdowns (ninth in the NFL). He has been targeted 99 times and averages 5.1 receptions per game in 14 games played.
• Through 14 games played this season, Tyler Warren has 63 catches (4.5 receptions per game on 6.4 targets per game) for 718 yards and four receiving touchdowns.
• Alec Pierce has been targeted 68 times, resulting in 39 catches for 785 yards .

Defense

• Germaine Pratt's 2025 effort includes 108 tackles and 6.0 TFL through 13 games. He leads the Colts in tackles.
• Zaire Franklin has 104 tackles, 5.0 TFL, and two sacks. He is second on the Colts in tackles.
• Nick Cross has 95 tackles, 4.0 TFL, 2.5 sacks, and one interception in the 2025 campaign. He is third on the Colts in tackles.
• Laiatu Latu has totaled 6.5 sacks (first on the Colts) as well as 10.0 TFL, 38 tackles, and three interceptions.

FOX Sports created this story using technology provided by Data Skrive and data from Sportradar.

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