NFL Week 16 will conclude with the San Francisco 49ers (10-4) vs. the Indianapolis Colts (8-6) clashing on Monday Night Football. This matchup is set for 8:15 p.m. ET, on ABC and ESPN.
The 49ers have clinched a playoff berth, but during the Colts' four-game losing streak, they lost first place in the AFC South and are currently out of the playoff picture. Each game is crucial for Indy’s playoff hopes.
Below, we'll break down our 49ers vs. Colts prediction on the spread for the Monday Night Football matchup with PrizePicks Team Picks, where you can earn money by picking on teams to win, spreads, and totals in every NFL game.
49ers vs. Colts Prediction on Spread
The 49ers and Colts meet for the 46th time, with Indianapolis holding a 27-19 lifetime record, including a five-game winning streak.
San Francisco comes into the game as 3.5-point favorites, returning a 1.75x payout on PrizePicks Team Picks if they cover.
Indianapolis is the home underdog, with a 2x payout if they cover the 3.5 points, and a 2.77x payout if they win outright.
- Spread: 49ers -3.5
- Over/Under: 45.5 (1.75x on Over)
- Game Winner Payout: 49ers 1.4x | Colts 2.77x
Team Picks data is live at the time of writing and is subject to change.
49ers vs. Colts Preview for Monday Night Football
Let's peel back the layers of this Monday night inter-conference matchup and breakdown boht sides of 49ers vs. Colts.
Indianapolis Colts Preview vs. 49ers
The Colts' ship is sinking fast. At one point, their 7-1 record had them as the top seed in the AFC, but they are 1-5 since and are currently out of the playoffs.
Indianapolis’ offensive performance might explain its recent decline. From Weeks 1-10, they led the league in EPA (0.183) and were second in success rate (51.0%).
During that time, RB Jonathan Taylor led the league with 1,443 rushing yards and 16 rushing TDs. Colts QB Daniel Jones led the league with 2,659 passing yards, but recently suffered a torn Achilles, ending his season.
Since Week 12, the offense ranks 26th in EPA (-0.066) and 28th in success rate (38.4%).
The Colts signed QB Philip Rivers out of retirement, and he’s playing in the NFL for the first time since 2020. With a 44-year-old starting quarterback, they could rely on Taylor, who has 20+ carries in three straight games.
JT has a favorable matchup against a 49ers’ run defense that has struggled in recent weeks, ranking 26th in rush EPA since Week 10 (-0.005).
San Francisco 49ers Preview vs. Indianapolis
49ers QB Brock Purdy’s return has the offense looking better, with the team averaging 27.0 points in the four games since his return, compared to 22.8 points with QB Mac Jones as the starter.
The biggest concern for Purdy is turnovers; his 12:7 TD:INT ratio is not excellent, and while he hasn’t thrown a pick in his last two games, it was against Cleveland, who ranks 16th in interceptions (10), and Tennessee, who ranks 27th.
This is an Indianapolis defense that has the fifth-most picks this season (12) and has an excellent pass rush that ranks tenth in pressure percentage (24.2%).
According to PFF, Purdy is prone to turning the ball over, and his 4 INTs under pressure are the fourth-most.
49ers vs. Colts: Final Spread Prediction
While Indianapolis hasn’t won in its last four games, it’s kept it close. Of their previous four losses, three have been by one possession. Now, they get what feels like a must-win game at home.
Rivers may not be too involved, with low expectations, playing more of a game-manager role; that may allow Taylor to be the playmaker he’s been throughout the season and keep the clock moving.
Make 49ers vs. Colts Picks on PrizePicks
The Colts will try to snap their four-game losing streak and stay in playoff contention on Monday Night Football, while the 49ers will look to solidify themselves as in the running in the NFC West.
With PrizePicks, you can win real money during the 2025 NFL season if your predictions are correct. On Team Picks — now available in 22 states — you can pick on teams to win, spreads, and totals, and cash in if you're right.
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