Preview: 49ers at Colts, Monday Night Football INDIANAPOLIS (Interstat) — A critical interconference clash with playoff implications awaits as the San Francisco 49ers visit the Indianapolis Colts on Monday, Dec. 22, 2025, at Lucas Oil Stadium. The visiting 49ers (10-4) enter on a three-game winning streak and are battling for NFC postseason positioning. The Colts (8-6), meanwhile, are clinging to AFC wild card hopes and are desperate to halt a two-game skid following a last-second 18-16 loss at Seattle. San Francisco’s surge has been fueled by quarterback Brock Purdy, who is playing efficient, dynamic football. In last week’s 37-24 win over Tennessee, Purdy completed 23 of 30 passes for 295 yards and three touchdowns, adding 44 yards on seven rushes. Over the last three games, he has accounted for five touchdowns with just one interception. The 49ers’ offense, also featuring running back Christian McCaffrey, presents a multifaceted challenge. Indianapolis will counter with veteran quarterback Philip Rivers, who was efficient but limited in yardage in the narrow loss to the Seahawks. The Colts’ offensive engine remains running back Jonathan Taylor, who rushed for 87 yards on 25 carries in that contest. The Colts’ season has been marked by volatility, with a four-game winning streak in October followed by inconsistent results. According to National Statistical’s game simulator, the Colts are projected to win 30-25. Oddsmakers have installed Indianapolis as a 5.5-point favorite. The over/under is set at 46.5 points. The matchup pits San Francisco’s momentum against an Indianapolis team in must-win mode at home. A 49ers victory would solidify their playoff standing, while a Colts defeat could severely damage their postseason chances with games against AFC South rivals Jacksonville and Houston looming to finish the season. Kickoff is set for 8:15 p.m. EST on ESPN.