Monday Night Football Predictions: 49ers vs Colts Picks, Odds & Best Bets for Week 16

San Francisco 49ers quarterback Brock Purdy (13) against the Arizona Cardinals at State Farm Stadium.

Andrew Wilsher

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Managing Editor of Pickswise. Born and raised in jolly old London, England, with an undying love for the NFL, NBA, soccer and horse racing. A big-time sports bettor who loves futures markets and backing underdogs. Long-suffering New York Jets fan. For Andrew Wilsher media enquiries, please email contact@pickswise.com.

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49ers vs Colts predictions & NFL MNF picks

Chris Farley’s 49ers vs Colts spread pick: Colts +6 (-110)

Philip Rivers will return to Monday Night Football in just his second week back and needless to say, this feels like it’ll be a highly entertaining watch. In his first start he played well, far above expectations considering he’s a 44-year old quarterback who hasn’t been in the league for five years. Rivers also had his first appearance against one of the toughest defenses in the NFL, a Seahawks’ group that ranks top-5 in EPA per pass. Shane Steichen gave Rivers an easy-to-follow gameplan which incorporated many short, simple throws to get him back in the fold, and the veteran went 18-27 for 120 yards for one touchdown and one interception.

Of course, that wasn’t a particularly impressive performance, but Rivers never looked rattled or out of his comfort zone. In fact he seemed to have command over the offense, calling audibles and vocally leading his comrades with the same ferocity he was known for in San Diego.

The Colts’ defense played very well last weekend, limiting the home-team Seahawks, one of the most potent offenses, to just 314 yards. A unit that ranks 11th in total defensive EPA, Indianapolis has its flaws on that side of the ball, particularly against opposing quarterbacks (ranked 14th in EPA per pass and permitting 7.1 yards per pass, 16th). We expect them to show their best form on Monday night, along with the rest of their squad, since their chances at a postseason run lie in the balance.

The 49ers won in Week 15 in what was an easy-breezy win for the most part, although they allowed the hapless Titans to eventually score 24 points. San Francisco sprinted out to a 31-10 lead and played more casually after that. They barely covered the spread (-12.5), but a late field goal with just two minutes left helped secure the needed margin. In general the 49ers are an average team with good leadership and mostly good quarterback play (4th in completion percentage, 10th in yards per pass), and they’re also fighting for their postseason spot in a crowded NFC West.

If the playoffs started today, the Niners would be in. They also have a favorable schedule remaining to round up their season, with two home games incoming in Weeks 17 and 18. The Colts are the more desperate team — since they are currently outside the playoff picture, meaning every game qualifies as a must win. They also have a difficult remaining schedule against two more AFC South opponents. We like the Colts to give it their all and to throw the kitchen sink at the Niners, plain and simple.

Chris Farley’s 49ers vs Colts total pick: Over 46.5 (-110)

The market is understandably in limbo over this total and we know why – it’s about Phillip Rivers. The 44-year old quarterback looked just fine in his first game back but it’s realistic to remain cautious about his ceiling. The Colts surround Rivers with plenty of offensive talent but Robert Saleh, the 49ers’ defensive coordinator, is an elite, veteran play-caller who will look to expose Rivers’ absence from the NFL for the past five years.

On the other hand, a bonafide offensive genius in Shane Steichen, who played a huge hand in building Philadelphia’s Super Bowl success, gets to grind all week with Rivers and the offense. The real clincher here is that San Francisco is the worst defense in the NFL when it comes to sacking the quarterback, making it happen on just 3.23% of plays. Perhaps even more concerning is they’re pedestrian against the run, ranked 21st in defensive EPA per rush and allowing 4.3 yards per rush (17th). In both regards, that paints a picture where Rivers and the Colts’ offense can move the ball methodically and without much pressure. For the former Chargers’ quarterback this is crucial, and we think it’ll aid the Indy offense throughout this contest. It doesn’t hurt that they’re at home on Monday.

Since Brock Purdy returned to the 49ers, there’s no denying that their offense has stabilized. In four games back he’s only turned it over in one contest, a weird three-interception display against the Panthers in Week 11. Otherwise he’s been steady: 83-117 (71%) and eight touchdowns. The Niners’ rushing attack has been far below expectations (3.5 yards per rush) and Indy is very good against enemy rushing attacks (4th in defensive EPA per rush). That just means the Niners will need to air it out more often, which should either lead to more first downs or the ball back in the Colts’ capable hands. While the market is floating awkwardly under the key number of 47, we’re happy to take the over.

Read NFL pro bettor Chris Farley’s full analysis for his 49ers vs Colts predictions for MNF, where he has hit 14 of his last 18 picks!

49ers vs Colts player prop bets

Prop Holliday’s best 49ers vs Colts player prop pick: Tyler Warren 4+ receptions & Jonathan Taylor 2+ receptions (+100)

For my best 49ers vs Colts player prop bet, I’ve pieced together a small parlay on the Colts side of this game and for a few reasons. For starters, Philip Rivers does not look like he will be pushing the ball down field much during his 2nd stint in Indianapolis. Based on what I saw last week, Rivers is in there to move the chains and get Jonathan Taylor in scoring position while the defense tries to win the turnover battle. Last week, Warren and Taylor combined for 10 targets and 6 receptions between the pair and the only change I see coming is getting the ball more in Tyler Warren’s hands.

Rivers had the 4th-lowest air yards per attempt last week (5.2), and while it can only improve, it would take a miracle to see him airing it out to deep and intermediate crossing routes at this stage of his career. Warren was the focal point of the offense the first few weeks of the season until Daniel Jones elevated his play and became more comfortable in the offense. I expect Rivers to have several plays with Warren as his first read and Taylor as his check down. The other side of this is that San Francisco jumps out to an early lead and the Colts become one-dimensional, loading up on the underneath targets to the 2 men mentioned above.

Don’t miss Prop Holliday’s best MNF player prop bets for 49ers vs Colts, targeting Jonathan Taylor and Tyler Warren

49ers vs Colts TD scorer best bet: George Kittle (SF) anytime touchdown scorer (+125)

A healthy George Kittle is good for football. After missing 5 of the first 6 weeks of the season, Kittle has put together 8 straight games of 4+ receptions, while finding the end zone 5 times. Christian McCaffrey overshadows Kittle in the passing game, but Kittle’s 26.5% target share since Week 10 is an indication that Brock Purdy has no problem throwing the ball in Kittle’s direction, especially against a lackluster Colts passing defense.

49ers vs Colts TNF TD scorer prediction: Tyler Warren (IND) anytime touchdown scorer (+280)

Let’s back the other tight end star in 49ers vs Colts for our 2nd TD scorer prediction. Tyler Warren was off to a strong start to the season, but his play has declined in recent weeks. Philip Rivers is most definitely not the answer for Warren to have success on MNF, but the Colts use him in a variety of ways, especially down in the red zone. If the Colts find themselves in a 4th and short inside the 5-yard line, look for Warren to tush-push his way in or have Rivers find him over the top of the defense.

Now check out the rest of JutPicks’ 49ers vs Colts touchdown scorer best bets

San Francisco 49ers vs Indianapolis Colts Parlay

After 2 winners on Saturday night at +650 and +407 odds, don’t miss our 49ers vs Colts parlay picks for MNF tonight!

49ers -5.5 over Colts (-108)

In Rivers’ first start of his unexpected 2025 comeback, Indianapolis actually managed to stay competitive at Seattle in an 18-16 loss. However, let’s pump the brakes on talk of Rivers being some kind of heroic grandfather. Yes, he accounted himself well all things considered – but he averaged just 4.4 yards per pass attempt and, for the most part, did little other than hand the ball off to Jonathan Taylor. Rivers now faces another stellar defense in the 49ers, who are giving up just 106.1 rushing yards per contest. You know that unit is going to stack the box and force Rivers rather than Taylor to beat it.

On the other side of the ball, San Francisco QB Brock Purdy has been turnover-free in 3 of 4 games since returning from injury. The Niners have won 4 games in a row, all by at least 11 points. Their last 6 victories have all been by double-digit margins.

George Kittle to score a touchdown (+120)

With Brandon Aiyuk and Ricky Pearsall sidelined by injuries, the 49ers’ wide receiver room is among the worst in the NFL. Kittle will likely have to do most of the heavy lifting – again – along with Christian McCaffrey in the pass-catching department. That is nothing new for the 32-year-old, who has scored 6 touchdowns in just 9 games this season. He has found the end zone 4 times in the last 5 contests, including once in last weekend’s victory over Tennessee. It’s also worth noting that the Colts have allowed the 11th-most fantasy points to tight ends in 2025.

George Kittle to record 80+ receiving yards (+156)

Kittle has made 45 catches for 484 yards through 9 games this year. He has recorded at least 67 receiving yards in 5 consecutive contests heading into Monday’s matchup, so asking him to reach the 80 mark does not seem overly exorbitant. Even though Indy’s defense is solid, this should be a relatively favorable matchup for Kittle. The Colts are 2nd-last in the NFL against the pass, surrendering 247.6 yards per game. By comparison, they are 6th against the run and 2nd in yards per rushing attempt allowed.