Dan Johnson takes you through his preview, prediction, and pick for NFL Week 16’s game between the Indianapolis Colts and the San Francisco 49ers on Monday Night Football.

Monday night lands in Indianapolis with the roof closed and the stakes loud. San Francisco is 10–4, already in, and still climbing for a cleaner seed. Indianapolis is 8–6, slipping in the AFC race, and playing from the edge. Brock Purdy (QB) brings the stable version of this offense, while Philip Rivers (QB) brings the emergency steering wheel. The game decides whether the 49ers keep rising and whether the Colts keep breathing. Below is my prediction for NFL Week 16’s game between the Indianapolis Colts and the San Francisco 49ers on Monday Night Football.

Here’s how I’ll play it. I’ll be pumping out these predictions for individual games all season, with plenty of coverage here on DraftKings Network. Follow my handle @dansby_edits for more betting plays.

Indianapolis still has a real upset path, and it starts with short fields. This is the time of year when one bad punt, one tipped ball, and one sudden return can rewrite a night. The Colts commit only 0.88 turnovers per game and create 1.12 takeaways per game, while the 49ers sit at 1.18 turnovers and only 0.76 takeaways. Turnover margin is the fastest way to flip a spread without “playing better.” Indy also begins drives at its own 29, while San Francisco starts at its own 23, and that six-yard head start matters. Field position is quiet leverage, and it matters more when the margins feel tight. The Colts’ early-down defense is also sturdier, producing 55.9% successful stops on first and second down, while San Francisco sits at 50.6%. That’s how underdogs keep the game in the same zip code. Add in a pass rush led by Laiatu Latu (EDGE) with 39 pressures and DeForest Buckner (DT) with 29, and this can turn into a turnover game. Monday night crowds don’t whisper when the pocket starts collapsing.

Indianapolis can also steal points with its pass-catchers if it finds the right matchups. Michael Pittman (WR) is the zone-volume anchor at a 23.8% target share against zone, and Tyler Warren (TE) sits right there at 21.3%. Alec Pierce (WR) is the explosives button, ripping 2.26 YPRR against zone, and that’s the one shot that can flip field position without a turnover. Josh Downs (WR) is the man-coverage trigger at a 25.0% target share against man, but this opponent lives in zone, so his path needs schemed leverage.

That said, the Colts need Rivers to survive stress, and his pressure-to-sack rate sits at 14.3%, double Purdy’s 6.7%. That’s the kind of split that shows up in the morning headlines. Indianapolis also loses the scramble cheat code that buoyed its rushing efficiency earlier, because Daniel Jones (QB) posted 0.359 EPA/rush on 45 attempts. Without that escape hatch, every broken play becomes a punt conversation. When the Colts fall behind the sticks, their recent offense has not climbed out. San Francisco’s defense has also been better at limiting yards after catch, allowing 4.45 YAC per completion, and Rivers lives on YAC at a 79.2% share. That’s a collision between style and opponent strength, not just a stat note. That profile forces longer drives, and longer drives run into third down. And third down is where playoff teams separate from playoff hopefuls.

49ers vs. Colts pick, best bet

Indianapolis still has a real upset path, and it starts with short fields. The Colts commit only 0.88 turnovers per game and create 1.12 takeaways per game, while the 49ers sit at 1.18 turnovers and only 0.76 takeaways. Indy also begins drives at its own 29, while San Francisco starts at its own 23, and that six-yard head start matters. The Colts’ early-down defense is also sturdier, producing 55.9% successful stops on first and second down, while San Francisco sits at 50.6%. Add in a pass rush led by Laiatu Latu (EDGE) with 39 pressures and DeForest Buckner (DT) with 29, and this can turn into a turnover game. That said, the Colts need Rivers to survive stress, and his pressure-to-sack rate sits at 14.3%, double Purdy’s 6.7%. Indianapolis also loses the scramble cheat code that buoyed its rushing efficiency earlier, because Daniel Jones (QB) posted 0.359 EPA/rush on 45 attempts. When the Colts fall behind the sticks, their recent offense has not climbed out. San Francisco’s defense has also been better at limiting yards after catch, allowing 4.45 YAC per completion, and Rivers lives on YAC at a 79.2% share. That profile forces longer drives, and longer drives run into third down.

DraftKings hangs San Francisco -5.5 and a 45.5 total, and the spread matches the current-state gap. San Francisco is playing winning football now, while Indianapolis is trending the wrong way on both sides of the ball. The Colts can shorten the game with Taylor, but the numbers still show San Francisco’s defense improving as Indianapolis’ run efficiency fades. Turnovers make this spread feel fragile, because the Colts have the edge in differential and in average starting position. San Francisco’s cleaner discipline helps counter that, with a 5.63% pre-snap penalty rate versus Indianapolis at 7.37%. Both kickers are steady, sitting above 93% on field goals, so missed points should not bail anybody out. The return game gives Indianapolis some extra juice overall, but San Francisco has been better on kick returns per play.

San Francisco should treat this like a passing game with protection answers, because Indianapolis creates pressure even without blitzing at a 35.0% clip. That’s why the 49ers should live in quick access throws and heavier sets, because Kittle punishes zone and helps the front. McCaffrey should stay heavily involved as a receiver, because his usage already lives in routes and red-zone work. Purdy should lean into rhythm throws, because he’s elite when clean and merely survivable when heat arrives. Indianapolis should open with Taylor and chase explosives on the ground, because its run explosive rate sits at 12.4% and San Francisco allows 2.84 yards after contact per run. The Colts should keep the pass game layered into zone, because San Francisco plays zone on 77.1% of dropbacks and it has been vulnerable there at 0.133 EPA allowed. Pittman and Warren can keep the chains moving in that space, while Pierce is the one player who can flip the geometry with 2.26 YPRR against zone. The Colts’ red-zone defense can hold up overall at a 54.9% TD rate allowed, but the goal-to-go defense has been softer at 72.0%. San Francisco’s goal-line defense has been sturdier at 64.7%, which matters if this becomes a short-field brawl. The script still lands on San Francisco sustaining drives, stealing third downs, and forcing Indianapolis into the exact pressure moments Rivers has not solved.

I’m laying the 5.5 with the 49ers because the QB stress response and third-down edge are decisive. A win also keeps San Francisco climbing the NFC board, while a loss tightens Indy’s playoff vise. I’ve got it 49ers 26, Colts 20.

Best bet: 49ers -5.5 (-110) at Colts

Tail it with me in the DKN Betting Group here!

I’m taking Tyler Warren 5+ receptions at +150 because the coverage math and the quarterback profile both shove targets into his lap. San Francisco plays zone on 77.1% of dropbacks, and Warren is built for that world with a 21.3% target share against zone and 1.94 yards per route run. Rivers is also living in the short game at a 5.5 aDOT with 79.2% of his yards coming after the catch, so the Colts’ completions are designed to be layered throws, not isolation fades. That’s exactly where Warren lives, and it’s also how Indianapolis survives when the pocket tightens. Rivers has been a disaster under pressure at -0.92 EPA per dropback with a 0.0% success rate, and his pressure-to-sack rate sits at 14.3%, so the ball has to come out on schedule. Warren is the cleanest schedule button against zone, and he stays involved near the goal line too, carrying heavy red-zone usage and a real inside-the-ten role. I’m not asking him to hit a ceiling game, just to be the first reliable outlet in a game where the Colts need completions to keep pace. At +150, five catches is the right bet shape.

Best prop lean: Tyler Warren 5+ receptions (+150)

Tail it with me in the DKN Betting Group here!