- This page contains affiliate links. We may earn a commission at no extra cost to you.
San Francisco (10-4-0) at Indianapolis (8-6-0)
- When: Dec 22 2025, 8:15 PM
- Where: Lucas Oil Stadium, Indianapolis, IN
- Where to watch: ESPN
- Last Meeting: IND 30-18, October 24th, 2021
San Francisco vs Indianapolis Preview & Prediction
Spread: Indianapolis -5.5
Moneyline: Indianapolis (-268
Total: 46.0
San Francisco 49ers Betting Overview
San Francisco heads into Monday night knowing exactly what is on the line. A win keeps their postseason path wide open and strengthens their push in a crowded NFC race. At 10-4, the 49ers are playing their best football of the season and come in riding strong momentum.
Brock Purdy looks increasingly comfortable as his health improves. Over the last several games, he has been efficient, decisive, and more mobile than usual. That added scrambling element has forced defenses to stay honest, opening throwing lanes and extending drives. When Purdy is calm and protected, San Francisco’s offense operates with balance and patience.
The 49ers are favored by 5.5, and much of that confidence comes from their ability to control games at home. Even with some recent issues against the run, San Francisco still thrives by jumping ahead early and forcing opponents to abandon their preferred game script.
Defensively, the injuries up front are a concern, but the 49ers are still opportunistic and aggressive. If they can limit explosive runs and create third and long situations, the advantage swings heavily in their favor.
Player Prop Pick 49ers: Brock Purdy over 243.5 passing yards – With Indianapolis dealing with injuries and likely playing from behind, Purdy should have steady volume throughout the game.
Indianapolis Colts Betting Overview
Indianapolis enters this matchup in survival mode. After a strong start to the season, the Colts have slid hard, dropping out of the division lead and into a must win situation. At 8-6, there is no margin left for error.
The Colts are leaning on veteran quarterback Philip Rivers to stabilize things. While he looked serviceable in his return, this will be a much tougher test against a disciplined San Francisco defense and in a hostile road environment. Protection issues remain a major concern, especially with multiple injuries along the offensive line.
The Colts’ best weapon remains their ground game. Jonathan Taylor continues to be the engine, capable of controlling tempo and keeping opposing offenses off the field. That approach becomes even more important against a San Francisco defense that has allowed yardage on the ground recently.
Indianapolis will try to shorten the game and keep things close, but falling behind early could force them into uncomfortable passing situations.
Player Prop Pick Colts: Jonathan Taylor over 97.5 rushing yards – Given San Francisco’s recent run defense struggles, Taylor should see heavy usage from the opening drive.
Betting Outlook & NFL Expert Prediction
San Francisco is favored by 5.5 with the total set at 46.0. Indianapolis should find some success running the ball, but San Francisco’s balance, quarterback play, and home field edge are difficult to overcome.
Expect the 49ers to gradually pull away as the game progresses, especially if Purdy continues his efficient play.
Final Score: 49ers 27, Colts 20
Lean: San Francisco -5.5
Total: Over 46.0
- NFL Football Odds source: MyBookie Sportsbook
- Get real-time live scores & latest betting odds here!
