Monday Night Football in Week 16 of the 2025 NFL campaign is a showdown between the San Francisco 49ers and Indianapolis Colts. It marks Philip Rivers’ second start of his comeback and his first in front of the home crowd. Indianapolis has slumped to an 8-6 record, so it needs a win in the worst way. This is a huge game for San Francisco, too, as it tries to stay in contention for either the NFC West title or a wild-card spot.
Let’s dive into my 49ers vs. Colts predictions.
San Francisco 49ers vs. Indianapolis Colts odds
Money line: 49ers -260 / Colts +210
Spread: 49ers -5.5 (-110) / Colts +5.5 (-110)
Total: Over 46.5 (-105) / Under 46.5 (-115)
San Fracisco 49ers vs. Indianapolis Colts best bet #1: 49ers -5.5 (-110)
Are you ready to put your faith in a 44-year-old grandfather and back the Colts to keep it close against the 49ers? Not me. It is true that Indianapolis was competitive at Seattle in Rivers’ 2025 debut, losing 18-16. Still, it’s not like Rivers set the world on fire. Sure, by the standards of a 44-year-old who had not played football since 2020, it was respectable. But Rivers averaged a mere 4.4 yards per pass attempt and for the most part did little other than hand the ball off to Jonathan Taylor.
The Colts now face another stellar defense in the Niners, who are surrendering only 106.1 rushing yards per game. San Francisco is certainly going to stack the box and force Rivers rather than Taylor to beat it. As for the 49ers’ offense, Brock Purdy has been turnover free in three of four games since returning from injury. Head coach Kyle Shanahan’s crew has won all four those contests with Purdy under center — all by at least 11 points. The Niners’ six most recent victories have all come by double-digit margins.
San Francisco 49ers vs. Indianapolis Colts best player prop bet: George Kittle Over 64.5 receiving yards (-110)
Wideouts Brandon Aiyuk and Ricky Pearsall are out for San Francisco, making its receiver room among the worst in the NFL. As usual, that means Kittle (and running back Christian McCaffrey) will have to do a lot of the heavy lifting in the pass-catching department for the visitors. The Colts have given up the eighth-fewest receiving yards to opposing running backs this season, so Kittle may have more opportunities than McCaffrey. The former Iowa standout is no stranger to stepping up for his team. He has made 45 catches for 484 yards and six TDs through nine games this season. Kittle has delivered at least 67 receiving yards in five consecutive contests.
Although the Colts’ defense is a very good unit, this projects as a favorable matchup for Kittle. Indianapolis is second-to-last in the league against the pass, allowing 247.6 yards per game. By comparison, it is No. 6 against the run and No. 2 in yards per rushing attempt allowed. As such, the 49ers will probably have to do a majority of their damage through the air on Monday Night Football.
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