Philip Rivers returns to Lucas Oil Stadium tonight to try and keep the Indianapolis Colts' playoff hopes alive against the San Francisco 49ers.
My 49ers vs. Colts predictions and NFL picks for Monday Night Football believe both offenses will shine under the roof of Lucas Oil Stadium on Monday, December 22.
49ers vs Colts prediction
49ers vs Colts best bet: Over 46.5 (-110)
This is a spot where context matters more than box scores, and it points clearly toward the Over.
The game shifts indoors, Philip Rivers gets another week to settle into this offense, and he’s no longer dealing with the chaos of Lumen Field. On the other side, the San Francisco 49ers are finally healthy on offense and could be one of the strongest units down the stretch.
Our Covers Predictions project this total at 52.1 points, and there’s nothing about the Indianapolis Colts’ pace of play with Rivers under center that suggests they’re slowing games down compared to their season averages.
Last week’s stat line may look modest at first glance, but 120 yards on 27 attempts still included eight throws of 10-plus yards and nine targets to running backs. That usage hints at a more aggressive approach moving forward, something Shane Steichen reinforced by noting that game plans will vary week to week.
San Francisco’s defense just allowed 24 points and 6.2 yards per play to Tennessee, and Brock Purdy looked sharp coming out of the bye. This team is also 6-3-1 to the Over at home or indoors, where offensive efficiency jumps.
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49ers vs Colts MNF same-game parlay
The Colts will have more confidence passing the ball and might be forced to after an easy week vs. Seattle, where they played in a neutral game script from start to finish.
Rivers threw a lot of balls at or behind the line of scrimmage, as RB targets accounted for nine throws. Those might move downfield on Monday, and it was Ty Warren who led all Colts pass catchers in targets last week with six.
More aggressive passing means more yards for the grandpa, and even Cam Ward moved the ball vs. this 49ers defense last week.
49ers vs Colts SGP
- Philip Rivers Over 163.5 passing yards
- Tyler Warren Over 4.5 receptions
- Over 46.5
Our big-ticket SGP: MNF Shootout
There are some great Indy TD prices as Rivers has a passing TD total of 0.5. Let's stay on the Warren train and get the TE for a TD after a team-high in targets last week, and hopefully fewer balls going to RBs.
George Kittle will not be stopped, especially with a QB who looked past his turf toe injury last week. He has five TDs over his last seven games and is coming off a season-high 88 yards last week.
Indy might keep pace for a bit, but the 49ers' offense might be in its best form of the season.
49ers vs Colts SGP
- Tyler Warren anytime touchdown
- George Kittle anytime touchdown
- Over 46.5
- 49ers -5.5
49ers vs Colts game predictions
49ers vs Colts moneyline prediction
I know the Colts are optimistic after last week's competitive game vs. the Seahawks as a 13-point dog, but if this offense has to chase points, which it didn't last week, it could be a different story. I can't see Rivers and this offense outlasting a rejuvenated Purdy and a healthy San Francisco offense right now.
49ers vs Colts spread prediction
This number has moved quite a bit. It was a flat -3 over the summer, reopened at -6 on Sunday night, and has since bounced between 5.5 and 6.5. Indianapolis was a 13-point road underdog last week, and some market ratings still have San Francisco as a 3.5-point underdog on a neutral field against Seattle, which feels stretched. The 49ers have been discounted all season, posting a 9-5 ATS record, and this is an offense built to win to margin, especially indoors. If Philip Rivers is forced to open things up this week, the mistake potential rises, which only strengthens the case for laying the number.
49ers vs Colts Over/Under prediction
I love this Over. It has been bet up from 45.5 to 46.5 and is trending to the key number of 47. The Colts might open up this playbook in the second week, with Rivers and the 49ers offense is a scary one with Purdy healthy out of the bye. An indoor game with a lot of offensive talent on both sides.
49ers vs Colts odds
- Spread: 49ers -5.5 | Colts +5.5
- Moneyline: 49ers -270 | Colts +220
- Over/Under: Over 46.5 | Under 46.5
49ers vs Colts betting trend to know
The 49ers have gone Under the total in just three of their 10 games at home or indoors this season. Find more NFL betting trends for 49ers vs. Colts.
How to watch 49ers vs Colts
| Location | Lucas Oil Stadium, Indianapolis, IN |
| Date | Monday, December 22, 2025 |
| Kickoff | 8:15 p.m. ET |
| TV | ESPN or ABC |
Learn how to live stream 49ers vs. Colts for free tonight.
49ers vs Colts latest injuries
49ers vs Colts weather
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More 49ers vs Colts picks from Covers
- 49ers vs. Colts props
- 49ers vs. Colts anytime touchdown scorer picks
- 49ers vs. Colts same-game parlay
- 49ers vs. Colts computer picks
- Philip Rivers odds and props
- Monday Night Football odds and betting lines
Odds are correct at the time of publishing and are subject to change.
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