Monday Night Football in Week 16 of the 2025 NFL campaign is a game between the San Francisco 49ers and the Indianapolis Colts. It marks Philip Rivers’ second start of his comeback and first in front of the home crowd. Indianapolis dropped to an 8-6 record, so they need a win badly. This is a big game for San Francisco, too, as it tries to stay in contention for the NFC West title or a wild card berth.
Let’s get into my predictions for the 49ers vs. Colts.
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 Francisco 49ers vs. Indianapolis Colts best bet #1: 49ers -5.5 (-110)
Are you ready to put your faith in the 44-year-old and back the Colts to keep them close against the 49ers? Not me. It’s true that Indianapolis was competing against Seattle in Rivers’ 2025 debut, losing 18-16. However, it is not like the River that burns the earth. Indeed, by the standards of a 44-year-old who hadn’t played football since 2020, it was respectable. But Rivers averaged just 4.4 yards per pass attempt and for the most part did little other than give Jonathan Taylor the ball.
The Colts now face another stellar defense in the Niners, who are only giving up 106.1 rushing yards per game. San Francisco will surely box and force Rivers instead of Taylor to shoot it. As for the 49ers’ offense, Brock Purdy has been without pay in three of four games since returning from injury. Coach Kyle Shanahan’s team has won all four contests with Purdy under center – all by at least 11 points. The Niners’ most recent victories have all come by double-digit margins.
San Francisco 49ers vs. Indianapolis Colts best player betting: George Kittle Over 64.5 receiving yards (-110)
Wideouts Brandon Aiyuk and Ricky Pearsall are out of San Francisco, making their receiver room among the worst in the NFL. As always, that means Kittle (and running back Christian McCaffrey) will have to do a lot of the heavy lifting for the visitors. The Colts have given up eight-fewest receiving yards to 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 45 catches for 484 yards and six TDs in nine games this season. Kittle has posted at least 67 receiving yards in five straight contests.
While the Colts’ defense is an excellent 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. In comparison, it is No. 6 against the run and No. 2 in yards per rushing attempt allowed. So, the 49ers will probably have to do a lot of damage in the air on Monday Night Football.
