San Francisco 49ers vs Indianapolis Colts Pick & Prediction – 12/22/2025

The San Francisco 49ers and Indianapolis Colts are set to face off on Monday Night Football in Week 16 of the NFL season. With the 49ers sporting a 10‑4 record and the Colts sitting at 8‑6, this Week 16 meeting in Indianapolis holds playoff implications for both clubs. San Francisco enters as a clear favorite on the road, as the Colts try to rebound from a recent losing streak due to instability at quarterback. Before kickoff from Indy, my 49ers vs Colts prediction can be found below.

Our 49ers vs Colts Pick

Game Snapshot

• Matchup: San Francisco 49ers vs Indianapolis Colts
• Date & Time: Monday, December 22, 2025, 8:15 PM
• Venue: Lucas Oil Stadium, Indianapolis, IN
• Broadcast: ESPN/ABC

Key Storylines

These teams are moving in opposite directions late in the regular season. The 49ers have won four games in a row and they have a shot to win the NFC West and claim the top seed in the NFC still. All four wins during the Niners’ current win streak have been by double-digits, though they were against softer competition than the Niners will face in this game.

The Colts have lost four games in a row going into Week 16. They lost starting quarterback Daniel Jones for the season and had to sign a previously retired Philip Rivers to replace him. The Colts haven’t scored over 20 points in a game during their current losing streak and will try to reverse that trend with a better offensive performance in this game.

Quarterback Play

San Francisco’s offense continues to hum with Brock Purdy back at quarterback. Purdy missed time due to injury earlier in the season and has come back to lead the Niners to solid showing after solid showing on offense. As long as Purdy stays healthy, the Niners have a legitimate shot to get back to the Super Bowl this year.

For the Colts, the quarterback picture currently revolves around 44‑year‑old Philip Rivers. Rivers’ first start since coming back saw him complete 18 of 27 passes for 120 yards, a touchdown, and an interception. Rivers will start again against the 49ers, and he will try to be more productive through the air than he was in his return to action.

Betting Trends

• The 49ers are 5‑1 against the spread in their last six outings.
• The Colts are 2‑4 against the spread in their last six games.
• San Francisco is 6-2 on the road this season.
• Indianapolis is 6-1 in their home games this year.

49ers vs Colts Model Projection

Final Thoughts

Jay Sanin

Jay Sanin is the GM and Head of Sports at ATS.io. He has been writing about sports gambling since 2013, handicapping tens of thousands of sporting events. He plays sides and totals aggressively across most sports and is more selective in player prop markets. He does his own modeling across most sports, and his family is jealous of how much time he spends on his precious spreadsheets.