49ers vs. Colts Week 16 Dunkel NFL Picks, Predictions and Odds

The San Francisco 49ers (10-4) are the favorites, expected to win by at least a field goal but less than a touchdown (currently -4.5) over the Indianapolis Colts (8-6). The 49ers have taken four games straight. The expected point total for the matchup is set at 46.5.

The 49ers rank 10th in scoring offense (24.6 points per game) and 11th in scoring defense (20.9 points allowed per game) this season. The Colts rank sixth in the NFL with 28 points per game on offense, and they rank 13th with 21.6 points given up per contest on defense.

49ers vs. Colts Odds and Game Time

• Date: Monday, December 22, 2025
• Time: 8:15 p.m. ET
• City: Indianapolis, Indiana
• Venue: Lucas Oil Stadium
• Total: 46.5 points
• Spread: 49ers -4.5
• Moneyline: 49ers (-230), Colts (+190)

How to watch 49ers vs. Colts

• TV Channel: ESPN
• Live Stream: Fubo

Betting the Over/Under: 49ers vs. Colts

• The 49ers and their opponents have scored more than 46.5 combined points eight times this season.
• So far this season, eight of San Francisco's 14 games have gone over the point total.
• The Colts have played nine games this season that have gone over 46.5 combined points scored.
• Indianapolis and its opponent have combined to go over the point total seven out of 14 times this year.
• The two teams combine to score 52.6 points per game, 6.1 more points than this matchup's total.
• These two teams together surrender 42.5 points per game, 4.0 fewer than this contest's total.

Betting the Spread: 49ers vs. Colts

• San Francisco is 9-5-0 ATS this season.
• San Francisco is 3-0 ATS this season when playing as at least 4.5-point favorites.
• The Colts are 8-6-0 ATS this year.
• Indianapolis has won each of its two games this year when playing as at least 4.5-point underdogs.
• At home this year, the Colts are 4-3 against the spread and 6-1 overall.
• In away games, the 49ers are 6-2 overall and 6-2 against the spread.
• Away from home, San Francisco is unbeaten ATS (1-0) as 4.5-point favorites or more.

Betting the Moneyline: 49ers vs. Colts

• San Francisco has won nine of the 10 games it was the moneyline favorite this season (90%).
• This season, the Colts have won two out of the five games in which they've been the underdog.
• San Francisco has won all three games it has played as a moneyline favorite with odds of -230 or shorter.
• Indianapolis has played as an underdog of +190 or more once this season and lost that game.
• The 49ers have a 69.7% chance to win this game based on the moneyline's implied probability.

Dunkel Prediction for 49ers vs. Colts

For more expert NFL picks, visit our Dunkel Index NFL Picks and Predictions.