Indiana Colts vs San Francisco 49ers Prediction, Preview, Injury Report and How to Watch

The Indiana Colts vs San Francisco 49ers prediction centers on a key Week 16 Monday Night Football matchup on December 22, 2025, at Lucas Oil Stadium in Indianapolis. Both teams enter with contrasting momentum as playoff positioning tightens.

San Francisco arrives on a four-game winning streak, while Indianapolis is trying to stop a late-season slide. Kickoff is scheduled for 8:15 p.m. ET, with national coverage on ESPN.

Indiana Colts vs San Francisco 49ers Prediction and Game Breakdown

The Indiana Colts vs San Francisco 49ers prediction leans heavily on current form and matchup efficiency. San Francisco is 10-4 and has won four straight games, each by multiple scores. The offense has averaged more than 27 points per game over the last three contests.

Indianapolis sits at 8-6 and has dropped four consecutive games, including a narrow loss at Seattle in Week 15. Veteran quarterback Philip Rivers will make his second straight start after coming out of retirement following Daniel Jones’ Achilles injury.

San Francisco ranks 10th in scoring offense at 24.6 points per game and 11th in scoring defense, allowing 20.9 points. The team has relied on balance, with Christian McCaffrey contributing heavily both on the ground and through the air.

The Colts score 28 points per game, sixth-best in the league, but production has slowed recently. Indianapolis has been held to 20 or fewer points in four straight games, raising concerns against a disciplined 49ers defense.

In the trenches, Indianapolis holds an advantage in the run game. The Colts rank top five in both rushing offense and rushing defense. Jonathan Taylor leads the league with 16 rushing touchdowns and remains the focal point of the offense.

San Francisco’s run defense has improved in recent weeks, allowing just over 106 rushing yards per game. However, the offense ranks near the bottom of the league in rushing efficiency, putting more pressure on the passing attack.

Injury-wise, the Colts will be without cornerback Sauce Gardner due to a calf injury. San Francisco will miss wide receiver Ricky Pearsall, while Christian McCaffrey is listed as resting but practiced fully and is expected to play.

Monday Night Football Context and Team Trends

This Monday Night Football matchup carries postseason implications for both teams. San Francisco is looking to secure playoff seeding and continue its late-season surge. Indianapolis is fighting to stay relevant in a crowded playoff picture.

Historically, the Colts have fared well at home against San Francisco, winning five straight meetings overall. Recent head-to-head matchups have been competitive, with Indianapolis holding a narrow scoring edge.

Quarterback play will be a defining factor. Brock Purdy has been efficient when healthy, while Mac Jones has also seen action for San Francisco this season. Rivers, meanwhile, benefits from a full week of preparation and a home environment.

Turnovers could decide the outcome. San Francisco has struggled in turnover margin this season, while Indianapolis ranks in the top half of the league in ball security and takeaways.

The Indiana Colts vs San Francisco 49ers prediction ultimately hinges on whether Indianapolis can control the run game and slow San Francisco’s passing rhythm. If the 49ers maintain balance and protect the ball, they hold a clear edge.

FYI (keeping you in the loop)-

Q1: What time does Colts vs 49ers start?

The game starts at 8:15 p.m. ET on Monday, December 22, 2025. It will be played at Lucas Oil Stadium in Indianapolis.

Q2: How can fans watch Colts vs 49ers live?

The game will air nationally on ESPN. Streaming options are available through ESPN-supported platforms.

Q3: Which players are key to the Colts vs 49ers matchup?

Jonathan Taylor and Christian McCaffrey are central to their teams’ offensive plans. Quarterback performance will also be critical.

Q4: Are there major injuries for Colts vs 49ers?

Indianapolis will be without Sauce Gardner. San Francisco will miss Ricky Pearsall, while most starters are expected to play.

Q5: Why is this Monday Night Football game important?

Both teams are competing for playoff positioning. The outcome could significantly impact late-season momentum.