The Colts are currently riding a four-game losing streak, which is the fourth-longest active streak in the league. If the Colts want to end that, they'll have to dominate the 49ers in these three areas on Monday night.

INDIANAPOLIS — The Indianapolis Colts and San Francisco 49ers understand the stakes on Monday night. Both find themselves in the throes of tense, tight division races where one more loss could eliminate them. Both are also trying to lock up playoff spots. And both face a daunting final three games against three potential playoff teams.

See who's in and who's out for the Week 16 matchup between the San Francisco 49ers and Indianapolis Colts on December 22, 2025.

The Indianapolis Colts have gone 1-5 in their last six games. Key players at impact positions are now out, and the team is sputtering to the finish line. They are significant underdogs to the San Francisco 49ers despite being at home on Monday Night Football in Week 16.

San Francisco 49ers wide receiver Ricky Pearsall has missed the team's first practice of the week due to knee and ankle injuries.

Find single game tickets to the San Francisco 49ers vs. Indianapolis Colts NFL Week 16 matchup on Monday, December 22, 2025 at Lucas Oil Stadium.

The Indianapolis Colts are at home in Week 16 for a Monday Night matchup with the San Francisco 49ers. So who do the NFL experts have winning this game? Perhaps not technically a must-win for the Colts,