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What happens if 49ers lose today against Colts on MNF in 2025 NFL Week 16?

The San Francisco 49ers are finally enjoying a strong season after dealing with multiple injuries last year, but they cannot afford to let their guard down and lose to the Indianapolis Colts, as a setback like that could push them further away from a bigger goal.

Brock Purdy stands on the sidelines vs the Chargers on August 23, 2025 in Santa Clara, California.
© Getty ImagesBrock Purdy stands on the sidelines vs the Chargers on August 23, 2025 in Santa Clara, California.

The San Francisco 49ers enter Monday Night Football with a 10-4 record and a strong winning streak, fully prepared to face the Indianapolis Colts, who could pose a real threat in Week 16. Even so, a loss would not necessarily be disastrous for San Francisco.

If the 49ers were to lose to the Colts, it would not mark the end of their postseason path. They have already secured a playoff spot after clinching a Wild Card berth thanks to the Lions’ loss to the Steelers on Sunday. Still, avoiding a loss remains important as they continue to chase the top spot in the NFC West.

Last week, Brock Purdy threw for 295 passing yards and three touchdowns in a 37-24 home victory. That win marked the team’s fourth since Week 11. The streak includes two road wins for the 49ers, a 41-22 victory over the Cardinals and a 20-9 win against the Cleveland Browns.

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Standings and the path to winning the NFC West

Before the 49ers face the Colts in Week 16, the NFC West is led by the Seattle Seahawks with a 12-3 record. The Los Angeles Rams sit in second place at 11-4, while San Francisco is currently third. The 49ers not only hold a 10-4 overall record, but they also lead the division in wins against NFC West opponents with a 4-1 mark.

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The NFC West race is one of the most complicated scenarios in the league, with several possible outcomes still in play. The 49ers remain alive in the division race and could still win the NFC West and secure the top seed, as outlined on Fitz & Witz: “If the Rams win out, they win the NFC West and they’re the No. 1 seed. If Seattle wins and they win out, they’re the NFC West champs and the No. 1 seed,” the show explained.

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“If Seattle beats the Rams but the 49ers win out, which would mean the 49ers beat Seattle in Week 18, then the 49ers are not only the NFC West champions but also the No. 1 seed in the NFC. That seems crazy to me.”

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More than 20 years without beating the Colts

The 49ers have gone more than 20 years without defeating the Colts. Their last win in the series came in 2001, meaning San Francisco has not beaten Indianapolis in 24 years. The most recent matchup took place in San Francisco in 2021, when the home team lost 30-18. Purdy was not the quarterback at the time, as Jimmy Garoppolo started that game and finished with one touchdown and two interceptions.

The situation for the Colts is difficult. They will play at home with Philip Rivers at quarterback, and the team is currently in crisis. Indianapolis needs to avoid a loss even more urgently than San Francisco needs a win. The Colts have not won a game since Week 10, when they defeated the Falcons in Germany.

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The 49ers’ offense could have a favorable matchup against the Colts. San Francisco is averaging 24.6 points per game, ranking 10th in the NFL this season. Just as important, the defense is allowing only 20.9 points per game. The Colts have failed to score 20 points in each of their last three games.

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