2025 NFL Week 16 49ers-Colts line, odds: Expert reveals pick for matchup on Monday Night Football

The Indianapolis Colts will look to snap a four-game losing streak when they battle the San Francisco 49ers on Monday Night Football. San Francisco is coming off a 37-24 win over the Tennessee Titans on Sunday, while Indianapolis dropped an 18-16 decision at Seattle. The 49ers (10-4), who are third in the NFC West, are 6-2 on the road this year. The Colts (8-6), who are third in the AFC South, are 6-1 on their home field. Indianapolis will start 44-year-old Philip Rivers for a second week in a row.

Kickoff from Lucas Oil Stadium in Indianapolis is set for 8:15 p.m. ET. The Colts lead the all-time series 27-19, including wins in each of the last five meetings. San Francisco is a 6-point favorite in the latest 49ers vs. Colts odds, while the over/under for total points scored is set at 46.5.  

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Before making any 49ers vs. Colts picks, you NEED to see which side SportsLine NFL expert Micah Roberts is on, considering his mastery of 49ers picks.

Roberts has worked in the Las Vegas sportsbook industry for 20-plus years, including a 13-year run as Station Casinos' book director. Armed with an elaborate network of sources, Roberts has unmatched info in multiple sports. He is arguably the nation's premier NASCAR betting expert and was the first bookmaker to offer expanded NASCAR betting. Over the past four MLB seasons, Roberts is 416-367, returning $1,038 to $100 bettors.

Most importantly, Roberts has a read on the pulse of the 49ers. He is 18-4 (+1360) on his last 22 against-the-spread picks in games involving San Francisco.

Now, Roberts has locked in another confident against-the-spread pick for 49ers vs. Colts.

We can tell you he's leaning Under on the point total, but he knows a crucial X-factor makes one side of the spread a MUST-BACK! You ABSOLUTELY need to see what it is before locking in any picks of your own.

So who wins 49ers vs. Colts on Monday Night Football, and what x-factor makes one side of the spread hit HARD? ... Join SportsLine right now to see which side of the 49ers vs. Colts spread to back, all from the expert who is a blistering 18-4 in his last 22 San Francisco 49ers picks!

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