49ers-Colts Week 16 Monday Night Football Preview: Odds, lines, best bets

San Francisco49ers (-5.5) vs. Indianapolis Colts [Total: 46]

Game Overview

An interconference matchup between two teams trending in very different directions caps off the Week 16 slate. 

In an ultra-competitive NFC West, the 49ers have been surging at the right time, having won (and covered) each of their past four games. Not only does San Francisco hold the opportunity to clinch a playoff berth with a win over the Colts — if it hasn’t already pending Sunday’s results — there is also a scenario in which the 49ers can capture the division crown and No. 1 seed, should they win out.

Additionally, this matchup holds importance for bettors that sided with the over on the 49ers’ win total futures prior to the season. A victory here would push San Francisco over its 10.5-win line. However, a loss could put reaching that mark in jeopardy, as the 49ers face two tough opponents to close out the regular season with the Bears and Seahawks.

The Colts, however, haven’t been as fortunate. After starting the year off strong, they've lost four consecutive games since emerging from their bye in Week 11. Time is running out on Indianapolis to squeeze back into the playoff picture, currently seated on the bubble with oddsmakers pricing their chances to secure a playoff berth at +700 (at DraftKings). 

Calling 44-year-old Philip Rivers out of retirement nearly brought about an upset win over the Seahawks in Week 15, but difficulties moving the football and finding points underscored the difficulties this team has had offensively down the stretch. Since Week 12, the Colts rank just 26th in EPA per play.

At the same time, that span has included matchups against three of the top four-highest ranked defenses in EPA per play allowed. That won’t be the case facing the 49ers, who rank 24th in EPA per play allowed without Fred Warner and Nick Bosa on the field.

However, the 49ers do project much more favorably in this matchup, even as road favorites. That’s something PFF’s Judah Fortgang highlighted with his game market bet of the week during the PFF Betting Show.

QB Brock Purdy, San Francisco 49ers: Over 240.5 passing yards (-115)

After throwing for 200 yards or fewer in his first three games since returning from injury, Brock Purdy found his rhythm in Week 15, putting up 295 yards through the air and earning his highest PFF passing grade (90.7) since Week 3 of the 2024 season. His 9.8 yards-per-attempt-mark was his most efficient performance of the season, a credit to his renewed ability to push the ball down the field.

This matchup against the Colts poses a strong opportunity for Purdy to have another efficient day through the air. Indianapolis has struggled to limit passers this season, having surrendered the third-most passing yardage in the NFL. Since Week 12, the Colts have permitted over 240 pass yards to each quarterback they’ve faced, having given up 7.74 yards per attempt on average.

To make matters worse for this Colts coverage unit, it’ll be left without its top two cornerbacks: Charvarius Ward was placed on injured reserve after sustaining his third concussion of the season, and Sauce Gardner is still dealing with a calf injury. Without them, this defense turns to Mekhi Blackmon and undrafted rookie Johnathan Edwards to man the outside cornerback spots — both of which maintain sub-50.0 PFF coverage grades.