Indianapolis Colts vs San Francisco 49ers Prediction 12/22/25 NFL Picks Today

The San Francisco 49ers and the Indianapolis Colts meet in week 16 NFL action from Lucas Oil Stadium on Monday. We will look at this from a betting perspective and determine the best bets for this game. Here’s a San Francisco 49ers vs. Indianapolis Colts prediction.

San Francisco 49ers Recap

The San Francisco 49ers come into this game looking to build on their 37-24 win over Tennessee last time out to sit at 10-4 this season. After this game, San Francisco will head home for a game against the Chicago Bears.

49ers Win 4 In A Row

Mac Jones has thrown for 2,151 yards, 13 touchdowns and 6 interceptions on 69.6% passing while Brock Purdy has thrown for 1,442 yards, 12 touchdowns and 7 interceptions on 67.9% passing. Christian McCaffrey has a team-high 922 rushing yards while also leading the 49ers in receiving with 86 grabs for 820 yards and 5 touchdowns. Ricky Pearsall has 443 receiving yards and 31 receptions while Kendrick Bourne has 499 receiving yards and Jauan Jennings has 495 receiving yards and 7 TDs. George Kittle also has 484 receiving yards and 45 catches along with 6 touchdowns this season. Three more 49ers have 150+ receiving yards as well on the year. On defense, Dee Winters has a team-high 89 total tackles. Bryce Huff and Clelin Ferrell each have a team-high 4 sacks. As a unit, San Francisco’s defense has combined for 16 sacks and 5 interceptions so far this season. 

Why the San Francisco 49ers will win

• The Colts have lost each of their last 11 games as underdogs against NFC opponents.
• The 49ers have won each of their last six games against AFC opponents on a losing streak.
• The Colts have failed to cover the spread in seven of their last eight games as underdogs against NFC opponents.
• The 49ers have covered the spread in each of their last five games as road favorites.

San Francisco 49ers Player Prop Facts

• Brian Robinson has recorded 24+ rushing yards in nine of his 10 previous December appearances.
• Brock Purdy has recorded 295+ passing yards in four of the 49ers’ last five December games.
• Brock Purdy has recorded 23+ completions in each of the 49ers’ last three December games.
• Brian Robinson has recorded 69+ rushing and receiving yards in five of his six previous December appearances with his team as a favorite.
• Jauan Jennings has recorded 24+ receiving yards in each of his last nine appearances against AFC opponents.
• Brandon Aiyuk has scored at least one touchdown in seven of his last eight regular season road appearances against AFC opponents.
• Heading into Week 16, Ji’Ayir Brown has recorded the equal-most interceptions in a single game this season (2 vs Panthers, Week 12).

Indianapolis Colts Recap

The Indianapolis Colts come into this game looking to rebound from an 18-16 loss to Seattle last time out to sit at 8-6 this season. After this game, Indianapolis will take on the Jacksonville Jaguars at home.

Colts Lose 4 In A Row

Philip Rivers has thrown for 120 yards, a touchdown and an interception on 66.7% passing and Jonathan Taylor has rushed for 1,443 yards and 16 touchdowns to lead the Colts on the ground. Alec Pierce has a team-high 785 receiving yards while Michael Pittman Jr. has 72 catches for 725 yards and 7 touchdowns. Tyler Warren’s added 63 catches for 718 yards and 4 touchdowns while Josh Downs has 406 receiving yards with 4 TDs and Taylor has 318 receiving yards as well this season. On defense, Zaire Franklin has a team-high 104 total tackles with 52 solo tackles while Cam Bynum and Laiatu Latu each have a team-high 3 interceptions for the Colts’ defense so far this season. Latu also has a team-high 6.5 sacks while DeForest Buckner and Kwity Paye each have 4 sacks as well this year. As a unit, Indianapolis’ defense has combined for 36 sacks and 12 interceptions so far this season.

Why the Indianapolis Colts will win

• The underdogs have won four of the 49ers’ last five Week 16 games.
• The 49ers have lost each of their last five games without Kendrick Bourne.
• The Colts have covered the spread in each of their last four games without Jonathan Taylor.
• The 49ers have failed to cover the spread in each of their last four games in December.

Indianapolis Colts Player Prop Facts

• Tyler Warren has recorded 44+ receiving yards in five of the Colts’ last six games at Lucas Oil Stadium.
• Philip Rivers has recorded 181+ passing yards in each of his last 18 December home appearances.
• Philip Rivers has recorded 18+ completions in each of his last 13 appearances with his team as an underdog.
• Jonathan Taylor has scored at least one touchdown in each of his four previous December home appearances.
• Jonathan Taylor has recorded 121+ rushing and receiving yards in four of the Colts’ last five games at Lucas Oil Stadium.
• Heading into Week 16, Jonathan Taylor ranks 1st in the NFL in rushing yards (1443) this season.

Total Points Facts

• Seven of the 49ers’ last eight road games without Brock Purdy have gone OVER the total points line.
• Each of the Colts’ last four games as home underdogs following a loss have gone OVER the total points line.

San Francisco 49ers vs. Indianapolis Colts Prediction

I’m on the under in this game. I get the case to be made for either side here, but the Colts didn’t look great offensively with Philip Rivers at QB last week despite almost beating Seattle as it was more the defense that held strong and did it’s part, and it’s going to have to again here most likely. On the other side, San Francisco’s defense has been holding strong as well, and I think that this is going to be a physical, ugly, game that the first to 20 wins. Give me the under here.