Following a 7-1 start to the season, the Indianapolis Colts were considered a lock to make the 2025 NFL Playoffs. However, the Colts are currently facing catastrophe, now trailing Houston by one game for the final AFC playoff spot.
QB Daniel Jones has gone from an MVP and Comeback Player of the Year candidate to the injured reserve. Injuries have wiped out the Colts' QB room.
In turn, the Houston Texans and Jacksonville Jaguars got into gear in the AFC.
A dream season for the Colts quickly became a nightmare. On Monday night, things won’t get any easier against the San Francisco 49ers.
Of course, Monday Night Football is always a draw. Especially when a legacy brand such as the 49ers is involved, betting activity will be massive.
The anticipation of the Holiday break will further add to the appeal.
Get the latest NFL Week 16 news, check out the current betting lines for the games, and don’t miss Monday Night Football action, all with the best odds at BookMaker!
San Francisco 49ers at Indianapolis Colts Odds at Bookmaker
Lucas Oil Stadium is the venue for the matchup between the San Francisco 49ers and the Indianapolis Colts on Monday, December 22, 2025. Kickoff time is at 8:15 p.m. ET with television coverage on ABC and ESPN.
San Francisco opened as a 5.5-point favorite with Indianapolis as a 5.5-point dog.
San Francisco is a -255 moneyline chalk with Indianapolis at +210.
The 49ers and Colts opened with an o/u total of 46.5.
San Francisco 49ers
Last game, the San Francisco 49ers won 37-24 against the Tennessee Titans as 12.5-point home favorites. The game went over the total of 45.5.
San Francisco is 10-4 straight up, 9-5 against the spread, and 8-5-1 over/under the total.
San Francisco ranks 10th for total offense, 5th for passing, 25th for rushing, 11th for scoring, and 24th for fewest turnovers committed.
San Francisco ranks 16th for total defense, 22nd vs. the pass, 12th vs. the rush, 11th for fewest points allowed, and 31st for takeaways.
San Francisco has covered in four of its last four games. San Francisco went under the total in two of its last three matchups.
Indianapolis Colts
Last game, the Indianapolis Colts lost 18-16 against the Seattle Seahawks as 13-point road dogs. The game went under the total of 41.5.
Indianapolis is 8-6 straight up, 8-5-1 against the spread, and 7-7 over/under the total.
Overall, Indianapolis ranks 9th for total offense, 9th for passing, 6th for rushing, 6th for scoring, and 14th for fewest turnovers committed.
Indianapolis ranks 20th for total defense, 31st vs. the pass, 5th vs. the rush, 12th for fewest points allowed, and 10th for takeaways.
Late on, Indianapolis has covered two out of its most recent six games. Indianapolis went under the total in three of its last four matchups.
49ers at Colts Betting Trends
San Francisco has been a good betting value on the road.
The 49ers covered the spread in six of their most recent eight games.
The 49ers went over the total in seven of their most recent ten games.
Since their quarterback room imploded, the Colts lost betting value at home.
Indianapolis covered the spread in only one of its previous four home matchups.
The Colts went over the total in three of their last four home tilts.
In the series between the 49ers and Colts, Indianapolis covered four of its most recent five games against San Francisco.
The Colts and 49ers went over the total in their last two meetings.
Specifically at Indianapolis, the 49ers covered the spread in two of their most recent three visits.
Two of those three games went over the total.
49ers at Colts Best Bets
San Francisco is a sharp type of pick.
Wise Guys love a quality road team and the more advantageous price.
Since the loss of Jones, gamblers are abandoning the Colts as they implode.
The quarterback quandary makes Indianapolis a tough sell to gamblers.
On this occasion, the 49ers have the definitive advantage at quarterback with the NFL odds.
The 49ers are in much better form, looking like a championship team.
Main Pick: San Francisco 49ers
Over/Under Pick: Under the Total
Player Prop Picks: Brock Purdy Over the Passing Yards Total
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