by Rod Pearson
Thursday, Dec 18, 2025
Game Time: 8:15 pm ET, Monday, December 22, 2025
Venue: Lucas Oil Stadium, Indianapolis, IN
Where to Watch: ESPN, ABC
Opening Odds at USA Sportsbooks
DraftKings: Point Spread: 49ers -6.5, Colts +6.5; Over/Under: 46.5 points
Bet365: Point Spread: 49ers -6, Colts +6; Over/Under: 46.5 points
BetMGM: Point Spread: 49ers -6.5, Colts +6.5; Over/Under: 46.5 points
Season Record
San Francisco 49ers: 10-4 (3rd place, NFC West)
Indianapolis Colts: 8-6 (3rd place, AFC South)
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Recent Form
San Francisco 49ers: won their last game at home against the Tennessee Titans 37-24.
Indianapolis Colts: lost their last game on the road against the Seattle Seahawks 18-16.
San Francisco 49ers vs Indianapolis Colts Preview and Analysis
The 49ers are entering this game with a 10-4 record overall and they have a 4-1 record in their divisional games too. They are 4-2 in their home games, 6-2 in their road games, and they are also 0-0 in their neutral site games this season, but they will be on the road for this game. They won their last game against the Tennessee Titans 37-24. Brock Purdy was the starting QB and he completed 23/30 passes for 295 passing yards, 3 touchdowns, and 0 interceptions. Christian McCaffrey led the team in rushing yards with 73 and 1 TD. Ricky Pearsall led the receivers with 96 receiving yards on 6 receptions. Malik Mustapha led the defense in that game with 6 solo tackles and 4 assisted tackles while no one on the defense recorded a sack for them. No one on the defense came away with an interception for them in that one.
The Colts are entering this game with an 8-6 record overall and they have a 2-2 record in their divisional games too. They are 5-1 in their home games, 2-5 in their road games, and they are also 1-0 in their neutral site games this season, but they will be at home for this game. They lost their last game against the Seattle Seahawks 18-16. Philip Rivers was the starting QB and he completed 18/27 passes for 120 passing yards, 1 touchdown, and 1 interception. Jonathan Taylor led the team in rushing yards with 87. Ameer Abdullah led the receivers with 32 receiving yards on 5 receptions. Zaire Franklin led the defense in that game with 7 solo tackles and 3 assisted tackles while Laiatu Latu led the defense in sacks with 1. No one on the defense came away with an interception for them in that one.
49ers vs Colts Prediction
The current betting odds have the 49ers listed as a 6.5 point favorite in this game according to Draftkings Sportsbook. The 49ers have looked really good in their games this season with their 10-4 record overall, but that record has them right near the bottom of the NFC West in a competitive division. They have been a good road team this year too with their 6-2 road record. Meanwhile, the Colts have looked good in their games this season with their 8-6 record overall, but that record has them right near the bottom of the AFC South in a competitive division. They have looked a lot better on their home field too with their 5-1 home record this season. The Colts are off an 18-16 loss to the Seahawks in their last one and they didn't look bad in that loss, but they have been a bit of a disaster lately. They lost their starting QB to injury and they have been dealing with other injuries now too. Rivers wasn't terrible in his first game back in years, but the offense still wasn't good and it isn't going to look any better against this 49ers defense. The 49ers offense has also looked a lot better lately with Purdy starting to get into a groove again, and they are still alive to win the division so they are going to bring their best effort. The best way to place a bet here is on the 49ers to cover the spread in this game.
49ers Colts Prediction: Our NFL Pick for Monday, December 22, 2025 (8:15 pm ET start time) is 49ers 28 Colts 17.
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NFL Betting Trends
San Francisco 49ers: 12-6 ATS as a road favorite. 10-5 ATS as a road favorite of 7 points or less. 4-1 ATS on the road vs. poor passing defenses - allowing 235 or more passing yards/game. 13-6 OVER in a road game where the total is between 42.5 and 49 points.
Indianapolis Colts: 4-9 ATS in non-conference games. 1-4 ATS vs. good passing teams averaging 7 or more passing yards/att. 2-6 ATS vs. good offensive teams - scoring 24 or more points/game. 8-3 OVER as a home underdog of 7 points or less.
Key Injuries
San Francisco 49ers: None.
Indianapolis Colts: None.
Notable Quotes
“For us every single game, with the guys that we have on the field, that’s our standard is to go out to move the ball, put up points, regardless of who we’re playing. We know that we’re talented and we have guys across the board — receiver, tight end, running back. For us, that’s always going to be our standard.” - Brock Purdy after their win against the Titans in their last game.
“It was exciting. Shoot, it was exciting to take a 13-3 lead. But first off, our play that we kind of had all week in the red zone in that area on that down and distance on that hash, we practiced in the exact same spot this week. So, when things go like that, they fire you up. Obviously, you throw in the fact that it’s been 1,800 days since throwing a touchdown or interception for that matter. So, yeah, both of those boxes were checked.” - Philip Rivers after their loss against the Seahawks in their last game.
Starting Lineups
San Francisco 49ers
WR Bourne, Kendrick
WR Jennings, Jauan
WR Robinson, Demarcus
TE Kittle, George
QB Purdy, Brock
RB McCaffrey, Christian
FB Juszczyk, Kyle
Indianapolis Colts
WR Pittman Jr., Michael
WR Pierce, Alec
WR Downs, Josh
TE Warren, Tyler
QB Rivers, Philip
RB Taylor, Jonathan
Statistical Leaders
San Francisco 49ers
Passing: Mac Jones (2,151)
Rushing: Christian McCaffrey (922)
Receiving: Christian McCaffrey (820)
Touchdowns: Christian McCaffrey (14)
Indianapolis Colts
Passing: Daniel Jones (3,101)
Rushing: Jonathan Taylor (1,443)
Receiving: Alec Pierce (785)
Touchdowns: Jonathan Taylor (18)
Coaches:
San Francisco 49ers: Kyle Shanahan (9th season)
Indianapolis Colts: Shane Steichen (3rd season)
Rod Pearson
About the Author:
Rod Pearson has been a rabid sports fan his entire life. He grew up in Ontario, and was skilled in both hockey and baseball, and pitched in an elite baseball league for many years. In 2022, Rod decided to hang up his glove, so that he could write about the sports he loves -- but from a gambling perspective. Join Rod every day as he breaks down the games to find the best betting value.
