Here is the Pickwatch BetSmart Preview for the San Francisco 49ers vs. Indianapolis Colts game in Week 16 of the 2025 NFL Season.

San Francisco 49ers vs. Indianapolis Colts Game Info

Date: Monday, December 22, 2025
Time: 8:15 PM ET
Location: Lucas Oil Stadium — Indianapolis, Indiana
TV: ESPN/ABC

49ers vs. Colts Betting Odds

Point Spread
- 49ers -5.5
- Colts +5.5
Moneyline
- 49ers -250
- Colts +180
Total
- Over/Under 46

Season Betting Records

Moneyline
- 49ers: 10-4
- Colts: 8-6
Against the Spread
- 49ers: 8-5-1
- Colts: 7-5-2
Totals (Over-Under)
- 49ers: 8-5-1
- Colts: 7-7

San Francisco 49ers (10-4) @ Indianapolis Colts (8-6) Preview

San Francisco enters tonight’s matchup looking to reassert control after an uneven stretch, but their formula remains clear: physical defense, efficient early-down offense, and explosive playmaking when matchups present themselves. When the 49ers protect the quarterback and stay on schedule, their offense becomes extremely difficult to slow, especially with the run game setting up play-action. Defensively, San Francisco continues to rely on pressure without heavy blitzing and strong coverage discipline over the middle of the field.

Indianapolis counters with an offense that has shown flashes of explosiveness but remains inconsistent drive-to-drive. The Colts are at their best when they establish tempo early and use the run game to keep the defense honest, opening up intermediate throws and designed movement for the quarterback. Defensively, Indianapolis has been aggressive up front but vulnerable to sustained drives, making tackling efficiency and third-down defense critical tonight.

With the game indoors, weather won’t factor into the equation, keeping the full playbook open for both offenses. From a betting perspective, San Francisco’s overall consistency and defensive edge make them rightful favorites, but Indianapolis’ ability to generate explosive plays at home gives them a path to staying competitive if they protect the ball. Expect the outcome to hinge on red-zone execution and whether the Colts can limit San Francisco’s efficiency on early downs.

49ers/Colts Head-to-Head (H2H) Stats and Analysis

The San Francisco 49ers lead the all-time series 27-19 vs. the Indianapolis Colts. Here are the last 5 meetings:

Indianapolis Colts 30, San Francisco 49ers 18 — October 24, 2021
Indianapolis Colts 26, San Francisco 49ers 23 (OT) — October 8, 2017
Indianapolis Colts 27, San Francisco 49ers 7 — September 22, 2013
Indianapolis Colts 18, San Francisco 49ers 14 — November 1, 2009
Indianapolis Colts 28, San Francisco 49ers 3 — October 9, 2005

BetSmart Betting Rundown

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NOTE: All available bets are as of time of publication. Odds and lines change often, so be sure to check each subsequent Pickwatch betting tool for the latest numbers.

Arbitrage

Our Arbitrage Betting Tool is currently identifying 3 arbitrage betting opportunities for guaranteed profit.

Middles

Our Middle Betting Tool is currently identifying 39 middle betting opportunities.

Positive EV

Our Positive EV Betting Tool is currently identifying 18 different positive expected value wagers, and provided data on the expected value percentrage, and how often the bet has hit in the last 5, 10 and 15 games.

Player Props

Our Prop Finder Tool is currently identifying 233 different player prop bets, and provided data on how often each player has hit the specific prop in the last 5, 10 and 15 games.

49ers vs. Colts: Expert Picks

Visit our Expert Picks page to view picks and data from over 200 experts to see where the consensus is on the 49ers vs. Colts moneyline, point spread and total points.