Week 16 of the NFL season concludes on Monday Night Football as we're set to bring you a betting prediction and pick for this upcoming tilt. The San Francisco 49ers (10-4) will visit the Indianapolis Colts (8-6) in a pivotal showdown for both teams ahead of the NFL Playoffs. Check our NFL odds series for the 49ers-Colts prediction and pick.
The San Francisco 49ers are third in the NFC West and occupy the sixth slot in the Playoff Picture, pending the results of the Rams-Seahawks TNF game. They took down the Tennessee Titans 37-24 in Week 15 and will search for their fifth-straight win as the betting favorites on the road.
The Indianapolis Colts are third in the AFC South, the last team on the bubble outside of playoff contention. After most recently falling to the Seattle Seahawks 18-16 for their fourth-straight loss, they stand with a 25% chance to make the playoffs if they can win this game at home.
NFL odds courtesy of DraftKings
49ers vs. Colts Monday Night Football Odds
San Francisco 49ers: -5.5 (-115)
Indianapolis Colts: +5.5 (-105)
Over: 46.5 (-102)
Under: 46.5 (-118)
49ers vs. Colts Key Injuries
*practice status as of Thursday, December 18, 2025. Subject to change*
San Francisco: LB Tatum Bethune, Limited (ankle) / CB Renardo Green, Limited (neck) / DE Yetur Gross-Matos, Limited (hamstring) / DT Sam Okuayinonu, Limited (ankle) / OT Spencer Buford, DNP (knee, ankle) / DT Jordan Elliott, DNP (knee) / LB Nick Martin, DNP (concussion) / RB Christian McCaffrey, DNP (rest) / WR Ricky Pearsall, DNP (knee, ankle) / OT Trent Williams, DNP (rest)
Indianapolis: QB Anthony Richardson, Limited (eye) / WR Alec Pierce, Limited (achilles) / OT Bernhard Raimann, DNP (elbow) / LB Germaine Pratt, DNP (personal) / WR Anthony Gould, DNP (foot) / CB Sauce Gardner, DNP (calf) / WR Josh Downs, DNP (personal)
49ers vs. Colts Betting Trends
- The Indianapolis Colts are 6-1 at home. The San Francisco 49ers are 6-2 on the road.
- The Colts are 8-6 ATS overall, 4-3 ATS at home. The 49ers are 9-5 ATS overall, 6-2 ATS on the road.
- The Colts are 3-0 outright, 3-0 ATS in their last three games against the 49ers.
- The 49ers are 5-1 ATS in their last six games.
- The Colts are 2-4 ATS in their last six games.
- The Colts have won eight of their last nine home games.
- The total has gone OVER in four of the 49er's last six games.
- The total has gone UNDER in four of the Colts' last six games.
Keys to 49ers vs. Colts Matchup
Both teams are riding opposite streaks heading into this one as the 49ers have won four-straight and the Colts have dropped their last four. The replacement QB Philip Rivers couldn't do enough to will the team to a win, but it's worth noting that Anthony Richardson has been practicing in a limited capacity and could make an appearance this season. While Rivers has been named the starter for Week 16, expect Richardson to see some work if the Colts are unable to win this game.
The main focus for the Colts will be getting the running game going behind Jonathan Taylor as their main source of offense for this team. Rivers is able to throw the check downs effectively, but they should really hinge on their All-Pro back to do the bulk of the work in this one. The Colts average the sixth-most rushing yards per game (128.5) and while the 49ers rank 12th in fewest yards allowed per game (106.1), we have to give the slight rushing edge to the Colts.
This all, of course, is negated with Christian McCaffrey on the other side of the ball, who's bound to have a big game in this must-win situation for the 49ers. QB Brock Purdy has gotten himself up to speed on the offensive flow for the season, all while McCaffrey remains the steady presence out of the backfield. Expect him to be the game changer for the 49ers in putting this game away early.
49ers vs. Colts Prediction and Pick
While Philip Rivers named the Colts' starter in Week 16, I don't expect this game to be too close with the way the 49ers' defense has played the last few weeks. They'll be much more unforgiving than the Seattle Seahawks now that they have some game tape of the 44-year old in action, so expect the pass rush of the 49ers to be coming quick during this one.
So long as the 49ers are able to contain Jonathan Taylor at the line of scrimmage and limit him to short gains up the middle, their offense should do the bulk of the work in scoring during this game. Honestly, the spread should be a bit wide, so we're going to roll with the San Francisco 49ers to cover the spread on the road as the total stays under.
Final 49ers-Colts Monday Night Football Prediction & Pick: San Francisco 49ers -5.5 (-115); UNDER 46.5 (-118)
