Monday Night Football in Week 16 of the 2025 NFL campaign features a showdown between the San Francisco 49ers and the Indianapolis Colts. It marks Philip Rivers’ second start of his comeback and his first in front of a home crowd. Indianapolis has fallen to an 8-6 record, so it needs a win in the worst possible way. This is also a huge game for San Francisco as it tries to stay in contention for the NFC West title or a wild card spot.
Let’s take a look at my predictions for the 49ers vs. Colts.
San Francisco 49ers vs. Indianapolis Colts odds
Moneyline: 49ers -260 / Colts +210
Spread: 49ers -5.5 (-110) / Stallions +5.5 (-110)
Total: Over 46.5 (-105) / Under 46.5 (-115)
San Francisco 49ers vs. Indianapolis Colts Best Bet No. 1: 49ers -5.5 (-110)
Are you ready to rely on a 44-year-old grandfather and root for the Colts to stay close to the 49ers? Not me. It’s true that Indianapolis was competitive in Seattle in Rivers’ 2025 debut, losing 18-16. Yet it’s not like Rivers set the world on fire. Sure, by the standards of a 44-year-old who hasn’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 pass the ball to Jonathan Taylor.
The Colts now face another great defense in the Niners, who are giving up just 106.1 rushing yards per game. San Francisco will certainly stack the box and force Rivers instead of Taylor to take him down. As for the 49ers offense, Brock Purdy has been turnover-free in three of the four games since returning from injury. Head coach Kyle Shanahan’s team has won all four games with Purdy under center – all by at least eleven points. The Niners’ six most recent wins 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, leaving the receiving 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 standing up for his team. He has 45 catches for 484 yards and six touchdowns in nine games this season. Kittle has delivered at least 67 receiving yards in five straight games.
While the Colts defense is a very good unit, this is a favorable matchup for Kittle. Indianapolis ranks second-to-last in the league against the pass, allowing 247.6 yards per game. By comparison, it’s No. 6 against the run and No. 2 in yards per rushing attempt allowed. As such, the 49ers will likely have to do most of their damage through the air on Monday Night Football.
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