49ers vs. Colts prediction, line, odds: Proven model releases spread pick for 2025 NFL Week 16 Monday Night Football

A cross-conference matchup on 'Monday Night Football' in NFL Week 16 has the Indianapolis Colts hosting the San Francisco 49ers. Indy (8-6) has lost four in a row, including an 18-16 defeat to Seattle last week in Philip Rivers' return after nearly five years of retirement. San Fran (10-4) has won four games in a row, most recently defeating Tennessee, 37-24, in Week 15. San Fran clinched a playoff spot on Sunday when the Lions lost to the Steelers. 

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Kickoff is at 8:15 p.m. ET from Lucas Oil Stadium in Indianapolis. The latest Colts vs. 49ers odds have San Francisco as the 4.5-point favorites, and the over/under for total points scored is 46.

Before making any 49ers vs. Colts picks, you NEED to see which side the proven SportsLine projection model is on.

The model, which simulates every NFL game 10,000 times, is up well over $7,000 for $100 players on top-rated NFL picks since its inception. The model enters Week 16 on a 52-37 run on top-rated picks dating back to 2024. Anybody following could have seen HUGE returns!

Now, the model has locked in another confident pick for Colts vs. Niners on 'Monday Night Football.'

We can tell you it's leaning Over the point total, but also says that one side of the spread hits well over 50% of the time! You ABSOLUTELY NEED to see which side to back before locking in any picks of your own.

So who wins Niners vs. Colts, and which side of the spread hits well over 50% of the time? ... Join SportsLine RIGHT NOW to see which side of the Colts vs. 49ers line to back, all from the model that has gone 52-37 on top-rated picks since 2024!

LIMITED TIME: Use promo code CHAMPIONSHIP to get your first month for $1 JOIN NOW.