NFL Monday Night Football Best Bets: 49ers vs Colts
Gabriel Santiago
Host · Writer
NFL season (and all its spoils) is in full throttle. Thankfully, there are betting opportunities nearly every day between now and next February, and we’ve got you covered for Week 16!
Where to Watch San Francisco 49ers vs. Indianapolis Colts
- Stadium: Lucas Oil Stadium
- Location: Indianapolis, IN
- Where to Watch: ESPN
- Time: 8:15 p.m. ET
San Francisco 49ers vs. Indianapolis Colts Betting Odds
- Spread: SF -5.5 (-115) | IND +5.5 (-105)
- Total: Over 46.5 (-105) | Under (-115)
- Moneyline: SF -270 | IND +220
San Francisco 49ers vs. Indianapolis Colts Kalshi Odds
- Chance: SF 69% | IND 31%
- Spread: SF -6.5 Yes (46¢) | No (55¢)
- Total: Over 45.5 Yes (54¢) | No (48¢)
After a pivotal weekend on the gridiron, the San Francisco 49ers (10-4) will visit the Indianapolis Colts (8-6) on Monday Night Football. This bid will have significant ramifications on both sides, so prepare to see a spirited effort.
San Francisco recently clinched its playoff spot, but this squad still has a chance to win the NFC West (+310 at FanDuel Sportsbook) and, incidentally, earn the conference’s top seed. Meanwhile, the Colts are looking to stop a four-game skid. Indianapolis is yielding nine-to-one odds to qualify for the postseason (per FanDuel) at this time, but a loss to the Niners at home will likely serve as an elimination.
Conversely, the 49ers are entering the “Circle City" on a four-game heater. This group has not lost since Brock Purdy (72.3 QBR) returned from turf toe. Throughout that span, San Francisco has averaged 31.0 PPG, up from its seasonal clip of 24.6 PPG. Running back Christian McCaffrey has been durable in 2025, having already posted over 1,700 all-purpose yards.
As baffling as it might sound, 44-year-old Philip Rivers is again the starting signal caller for Indy following four seasons of retirement. He returned to the field at Lucas Oil Stadium last Sunday, passing for 120 yards, one touchdown, and one interception. Rivers, a wily veteran, understands his role and opportunity to work behind the Colts’ booming offensive line. From there, a tailback like Jonathan Taylor certainly makes aspects more manageable.
I am not confident enough in the present group in Indianapolis to predict an upset, but I don’t mind taking 5.5 points (and as high as +6.5 points on Kalshi) with the Colts at home. Similar to last week, I think Indy will play conservatively, which can be effective with the current personnel. From there, the Niners have struggled to apply pressure on opposing quarterbacks, which has led them to give up 227.6 YPG through the air.
Best Bet: Colts +5.5 (-105)
The stats suggest we are dealing with two top-ten offenses in this bid, but I prefer the under 46.5 combined points. Obviously, the weather will not be a factor indoors, but I think both defenses are playing well enough to keep things contained.
The Colts are particularly strong against the run in 2025. After 14 outings, Indianapolis’ D has kept opposing offenses to only 95.1. That effort will be aided by the return of DeForest Buckner (neck) on Monday night. It will be a double reunion of sorts, as Buckner spent the first four seasons of his professional career with the 49ers.
If San Francisco’s ground game gets bottled up, Purdy will be forced to work with a limited receiving corps. Former first-round selection Ricky Pearsall is out with an ankle issue.
SportsGrid’s predictive model has under 46.5 total points labeled as a four-star play, which is its strongest rating for this game. Keep in mind: the Niners have surrendered just 15.75 PPG since November 16.
Best Bet: Under 46.5 (-115)
Swing for the Fences with SportsGrid’s free daily NFL Game Picks and NFL Prop Picks.
NFL Week 16 Best Bets: 49ers vs. Colts
- Colts +5.5
- Under 46.5 (-115)
Week 16 brings numerous opportunities to set a profitable tone on the gridiron. Best of luck!
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