49ers vs. Colts Prediction & MNF Best Bets (December 22, 2025)
Monday Night Football presents an interesting battle this week, as the San Francisco 49ers will be favored to down the Indianapolis Colts. Both teams will be fighting for their playoff lives, but the Niners will be sizable 5.5-point favorites even though they’re on the road.
A lot of that has to do with recent form. San Francisco has looked good lately, winning each of their last four games. Indy, meanwhile, is in dire straits. They are spiraling out of control with four straight losses, while last week they were forced to turn to 44-year-old Philip Rivers under center.
That move somehow almost led to an upset win in Seattle, but the Colts are now in must-win territory with their season hanging in the balance. Can old man Rivers do enough to extend their playoff lives for one more week, or will this experiment fail horribly under the bright lights of MNF?
I’ll go over the latest odds and key matchups to highlight my favorite picks before getting to my final 49ers vs. Colts prediction.
Game Info Snapshot
- Date & Location: Monday, December 2nd, 2025 | Kickoff at 7:15 pm ET (ESPN) at Lucas Oil Stadium in Indianapolis, IN
- Team records entering the game:
- San Francisco 49ers: 10-4
- Indianapolis Colts: 8-6
- Odds (from FanDuel)
- Spread: 49ers -5.5 (-112) | Colts +5.5 (-108)
- Moneyline: 49ers (-255) | Colts (+215)
- Total: Over 46.5 (-105) | Under 46.5 (-115)
The odds for this game indicate the 49ers are the likely winners. Being favored on the road usually is a strong sign you’re the better team, but being favored by almost a touchdown says quite a lot.
The game total is solid. Indy is at home, has a decent defense, and will try to play ball control offense, but this one could still get away from them. That keeps the total in check, but the 49ers have considerable offensive upside. You could argue there’s value on either side of this price.
Storylines to Watch
There are several key 49ers vs. Colts storylines that make this matchup compelling, but can also play into how you bet on the game. Here are the ones that stand out the most going into Monday Night Football:
- Rivers the Savior: Philip Rivers didn’t look great in his return following a five-year retirement, but the Colts need him to play well if they want to save their season. Will he look better in his second game, and can he actually right the ship for a free-falling team?
- Dominant Defense: San Francisco has not been elite on defense for much of the year, but they’ve been rounding into form lately, allowing 63 total points during their current four-game winning streak. Can they keep it up on the road?
- Explosive Back: A 44-year-old Rivers can’t elevate this Colts team, meaning stud running back Jonathan Taylor probably needs a massive game on MNF to save Indy’s season. It will be interesting to see if he can show out like he’s done so many times already in 2025.
Team Profiles
San Francisco 49ers
The 49ers have been a tough team to gauge this year. They got off to a nice 3-0 start earlier in the season, but then traded wins and losses over their next seven contests. It wasn’t until their recent four-game run where they started to look like a cohesive unit that bettors could have some faith in.
San Francisco can’t trust their defense like they used to, and the same can be said of their offensive line. Christian McCaffrey is still an effective red-zone threat and receiver out of the backfield, but the efficiency has simply not been there on the ground.
Still, despite their flaws, the Niners are 10-4 and still have a shot at the NFC West title and perhaps even the #1 seed in the NFC. Here’s a quick look at some key strengths that have allowed them to get in this position.
- Finish the Job: As noted, the Niners aren’t efficient everywhere this year, but they still know how to close out drives. They score 62% of the time once they pass the 20, giving them the 8th-best red-zone offense in pro football.
- Pass Attack: San Francisco has to throw more (55%) due to their ground game struggles, but the good news is they’ve been productive through the air. Despite Brock Purdy missing numerous games, the 49ers rank 10th in yards per pass, 4th in accuracy, and 4th overall through the air.
- No Mental Errors: The 49ers have always been well-coached ever since Kyle Shanahan arrived in the Bay Area, but just 5.2 penalties per game (2nd) means this team doesn’t shoot themselves in the foot too often.
Indianapolis Colts
The Colts looked like a surprise Super Bowl contender just a few weeks ago, as they raced out to a 7-1 start. They ran into some tough losses before losing Daniel Jones to a torn Achilles, however, taking a season of hope to one on the break of disaster.
Indy is such an interesting case, as they’ve been in almost all of their losses, falling to good Rams, Texans, and Seahawks teams by one score each. They are unraveling in a hurry, but they are well-coached and compete every single Sunday.
It may be too late for the Colts to save their season, but they are mathematically still alive. Let’s take a quick look at what they’ve done well at this point as they march into MNF.
- Finish the Job: Guess who is even better at closing out drives with a score? Yep, the Colts. Jonathan Taylor gives Indy a scoring menace, as this offense punches it in 64% of the time, giving them the league’s 6th-best RZ offense.
- Explosive Plays: Indy’s offense hasn’t been quite as good lately, but they can still explode on the ground. JT is the main reason why, as he’s churned out 1,443 yards on the ground and is running at a 5.3 yards per carry clip. It’s helped the Colts rank 6th in yards per rush (4.8), while this is the NFL’s 6th-best overall rush offense.
- Turnover Battle: The Colts are right around the top-10 when it comes to protecting the ball, and they’re an aggressive, opportunistic defense (9th) as well.
Key Matchups & Angles
Check out the key 49ers vs. Colts matchups:
- Indy’s pass defense vs. San Francisco’s pass offense: This is a total mismatch, as the 49ers are finally healthy and were already a tough passing game to stop. They come in ranked 4th in passing, while the Colts have struggled (31st) to stop opposing passing games and also lack a reliable pass rush.
- Indy’s rush offense vs. San Francisco’s run defense: JT is the key to this game. He can finish scoring drives in the red zone or bust off big runs. The Colts have a strong rushing offense because of him, but they’ll go up against a solid San Francisco run defense that doesn’t give up many rushing scores and ranks a respectable 12th against the run.
- San Francisco’s RZ offense vs. Indy’s RZ defense: While C-Mac and co. are elite at finishing drives with scores, Indy’s defense is a classic bend-but-don’t-break unit. The Colts can get thrown on, but they are tough on the run and batten down the hatches (9th) inside the 20.
Betting Trends & Odds Context
Take a look at the latest 49ers vs. Colts odds, per FanDuel:
| Team | Spread | Moneyline | Total |
|---|---|---|---|
49ers | -5.5 (-105) | -240 | Over 46.5 (-105) |
Colts | +5.5 (-115) | +198 | Under 46.5 (-115) |
Take a look at some key betting trends for this showdown:
- Public Betting: The public loves the 49ers in this one, with San Francisco presently getting 89% of the bets and 92% of the money.
- Record History: Indy and San Fran have waged war a surprising 46 times, with the Colts holding a 27-19 series advantage. The Colts won the most recent meeting 30-18 in 2021 and have won five in a row in the series.
- ATS Tidbits: The 49ers have been quite good (8-5-1) against the spread overall, while they are 6-2 ATS when favored and 6-2 ATS on the road. Indy has also been solid (7-5-2) against the spread, while they are 3-1-1 ATS as the underdog and 4-2 ATS at home.
Best Bets for 49ers vs. Colts
Pick 1: 49ers ATS -5.5 (-108) – 8/10 Confidence
Why We Like It
The easiest pick in this game is for the 49ers to win, but a -250 moneyline isn’t very appealing. The 5.5-point spread isn’t safe, but the Niners are the better team and are a total mismatch for a weak Indianapolis pass defense. An improved defense getting to feast on the 44-year-old Rivers also stands out as a key reason the 49ers are probably going to roll in this one.
Risks/What to Watch
Indy is at home, and they played the Seahawks very closely last week. They’ve been in pretty much every single game this year due to coaching and a strong running game. It’s entirely possible they hang around and keep this one close.
Pick 2: Under 46.5 (-120) – 7/10 Confidence
Why We Like It
If the Colts have their way, they will dictate the pace of this game with short passes and a lot of running. They’re also at home, and they do have a good run defense that could stifle San Francisco’s ground game. All things considered, you need to trust in Rivers a bit more than is comfortable if you want to hammer the Over in this spot.
Risks/What to Watch
San Francisco’s passing game should feast in this spot, while the defense could force a lot of turnovers against a guy in Rivers who is very much washed. The Niners put up 37 points in a blowout in their last game, meaning they could do a lot of the heavy-lifting on their own.
Pick 3: Prop Play – Jauan Jennings Over 60+ Receiving Yards (+112) – 7/10 Confidence
Why We Like It
The price for this yardage prop is insane, especially when you consider how much passing yardage this Indy defense allows. Ricky Pearsall is also banged up, so 49ers receivers like Jennings are going to get even more targets than usual.
Risks/What to Watch
San Francisco could opt to feed guys like McCaffrey or George Kittle. They could also run the ball more if they score early and are leading in this one.
49ers vs. Colts odds are shifting as bettors react to MNF pressure and playoff implications — track every line move, compare spreads and totals, and lock in the best value before kickoff at our top football betting sites.
Final Verdict: 49ers Stay in NFC West Hunt, Colts Crumble
The most obvious 49ers vs. Colts prediction to make is that San Francisco is going to find a way to win this game. Hats off to Philip Rivers for answering the call and stepping in like he did, but he definitely looks like someone that should have stayed retired.
Rivers is out of shape, doesn’t have as much mustard on his ball like he used to, and has happy feet in the pocket. He did well to avoid embarrassment against the Seahawks, but I don’t think the odds are great that he’ll accomplish that feat in successive games.
Jonathan Taylor and this game being played in Indy do combine to give the Colts a shot to keep it competitive, so a low-scoring game that doesn’t blow out is in the cards. Ultimately, I like the superior Niners to get the job done and win by a touchdown and cover in the process.
Final Score Prediction: 49ers 23, Colts 16
