San Francisco 49ers vs Indianapolis Colts Prediction 12/22/2025 Today’s NFL Picks

The San Francisco 49ers and Indianapolis Colts meet Monday in NFL action at Lucas Oil Stadium. Here’s a San Francisco 49ers vs Indianapolis Colts Prediction. This article will include a San Francisco 49ers vs Indianapolis Colts Pick.

San Francisco 49ers Betting Preview

The San Francisco 49ers beat the Browns and Titans, and play the Bears next. The San Francisco 49ers have won 4 straight games. Mac Jones is completing 69.6 percent of his passes for 2,151 yards, 13 touchdowns, and 6 interceptions. Kendrick Bourne and Christian McCaffrey have combined for 1,319 receiving yards and 5 touchdowns, while Jauan Jennings has 44 receptions.

The San Francisco 49ers ground game is averaging 101.4 yards per contest, and Christian McCaffrey leads the way with 922 yards and 9 touchdowns. Defensively, San Francisco is allowing 20.9 points and 333.6 yards per game. Dee Winters leads the San Francisco 49ers with 89 tackles, Bryce Huff has 4 sacks and Deommodore Lenoir has 2 interceptions.

Indianapolis Colts Betting Preview

The Indianapolis Colts lost to the Jaguars and Seahawks, and they play the Jaguars next. The Indianapolis Colts have lost 4 straight games. Philip Rivers is completing 66.7 percent of his passes for 120 yards, 1 touchdown, and 1 interception. Micheal Pittman Jr. and Alex Pierce have combined for 1,510 receiving yards and 9 touchdowns, while Tyler Warren has 63 receptions.

The Indianapolis Colts ground game is averaging 128.5 yards per contest, and Jonathan Taylor leads the way with 1,443 yards and 16 touchdowns. Defensively, Indianapolis is allowing 21.6 points and 342.7 yards per game. Zaire Franklin leads the Indianapolis Colts with 104 tackles, Laiatu Latu has 6.5 sacks and Cam Bynum has 3 interceptions.

Why the Indianapolis Colts will win

• The Colts have won seven of their last eight games at Lucas Oil Stadium.
• The 49ers have lost three of their last four Week 16 games as favorites.
• The Colts have covered the spread in each of their last four games as underdogs without Kwity Paye.
• The 49ers have failed to cover the spread in each of their last four games in December.
• The 49ers have lost the first half in three of their last four road games against AFC opponents.

Why the San Francisco 49ers will win

• The Colts have lost each of their last six games against opponents on a winning streak.
• The 49ers have won each of their last seven games as favorites without Brayden Willis.
• The Colts have failed to cover the spread in each of their last four Monday home games.
• The favorites have covered the spread in six of the 49ers’ last seven games.
• The Colts have lost the first half in seven of their last eight games as home underdogs.
• The Colts have lost the first quarter in five of their last six Week 16 home games against NFC opponents.

Total Points Facts

• Each of the 49ers’ last four road games without Christian McCaffrey have gone OVER the total points line.
• Each of the Colts’ last four Week 16 games as underdogs have gone UNDER the total points line.

Indianapolis Colts Player Prop Facts

• Philip Rivers has recorded 18+ completions in each of his last 10 regular season appearances with his team as an underdog.
• Philip Rivers has recorded 214+ passing yards in each of his last 16 home appearances against NFC opponents.
• Jonathan Taylor has scored at least one touchdown in each of his four previous December appearances at Lucas Oil Stadium.
• Jonathan Taylor has recorded 121+ rushing and receiving yards in each of the Colts’ last three games at Lucas Oil Stadium.
• Michael Pittman Jr. has recorded 31+ receiving yards in each of his last eight appearances with the Colts as home underdogs.
• Jonathan Taylor has recorded 83+ rushing yards in each of his four previous December appearances at Lucas Oil Stadium.
• Heading into Week 16, Jonathan Taylor ranks 1st in the NFL in touchdowns (18) this season.

San Francisco 49ers Player Prop Facts

• Brock Purdy has recorded 295+ passing yards in each of his three previous appearances against AFC South opponents.
• Brock Purdy has recorded 23+ completions in three of the 49ers’ last four December games as favorites against AFC opponents.
• Christian McCaffrey has scored at least one touchdown in 11 of his last 12 appearances with the 49ers as favorites against AFC opponents.
• George Kittle has recorded 67+ receiving yards in each of the 49ers’ last five games.
• Brock Purdy has recorded 11+ rushing yards in 19 of his last 22 appearances with the 49ers as favorites.
• Brian Robinson has recorded 53+ rushing and receiving yards in eight of his 10 previous December appearances.
• Heading into Week 16, Eddy Pineiro has recorded the most made field goals without a failed attempt this season (25).

Matchup/League Facts

• Heading into Week 16, the Colts have suffered the equal-most road losses by a margin of 10 points or less this season (4).
• Colts – only team with 3+ players to record 700+ receiving yards this season (Tyler Warren, Alec Pierce, Michael Pittman Jr.), heading into Week 16.
• Heading into Week 16, the 49ers rank 32nd in the NFL in average yards per punt (43.6) this season.
• Heading into Week 16, the 49ers have won the first quarter in each of their last four games – longest active streak in the league.

San Francisco 49ers vs Indianapolis Colts Prediction

The 49ers are playing their most consistent ball of the season and look to climb up the playoff rankings. The Colts are starting a 44-year-old quarterback for a second straight week. It’s not a surprise the line is what it is. However, let’s pump the brakes just a bit. During this four-game winning streak, the 49ers beat the Cardinals, Panthers, Browns, and Titans. Those teams are a combined 15-41 SU on the year. The Colts nearly upset the Seahawks on the road last week as two-touchdown underdogs.

Rivers has a full week of practice to get more comfortable, the defense is still respectable, and the Colts are 4-1 ATS as an underdog this season. Two of those covers were outright victories. The Colts are also fighting for their playoff lives, so this will be a motivated group. Since 2023, the 49ers are 4-6 ATS as road favorites of 5 or more points. I’ll grab the free touchdown with the Colts on Monday night.

Randy Chambers's Pick: Indianapolis Colts +6