NFL Upset Predictions and Picks for Week 6 (Bet Titans to Upset Colts in AFC South Duel)

The SI team had a great week of picking upset winners in Week 5 of the NFL season. Gilberto Manzano correctly bet on the Green Bay Packers to upset the Chicago Bears, and yours truly bet on the San Francisco 49ers to beat the Seattle Seahawks.

We move on to the Week 6 slate, and three writers have their upset picks locked in. Let's dive into them.

Gilberto Manzano, NFL Staff Writer
Iain MacMillan, Senior Editor, Betting
Peter Dewey, Associate Managing Editor, Betting

All odds listed are via DraftKings Sportsbook

Gilberto Manzano Week 6 Upset Pick

Houston Texans (+120) vs. Jacksonville Jaguars

First, let me pat myself on the back for finally getting an upset pick correctly. Now that I’ve regained your trust after my Packers-over-Bears pick came to fruition last week, do yourself a favor and take the new-look Texans over the London Jaguars. Houston gained confidence from beating up on Tennessee and landing wide receiver Marvin Harrison Jr. in a trade with Arizona. C.J. Stroud tends to play at his best when Nico Collins is on the field, but now he doesn’t have to lock in on him with the arrival of Harrison, who played with Stroud at Ohio State. More importantly, the Texans’ defense is back on track, and that could present trouble for the inconsistent Trevor Lawrence.

Iain MacMillan Week 6 Upset Pick

Tennessee Titans (+260) vs. Indianapolis Colts

It's time for the Titans to get their first win of the season.

You might be surprised to find out how many metrics these two teams rank similarly in, even some that the Titans outrank the Colts in, like net yards per play, which has the Titans at -0.7 and the Colts second-last in the NFL at -1.6.

Another interesting metric for this game is that the Titans have the second-highest run frequency in neutral game states, meaning on early downs in the middle of the game when they still have a more than 20% win probability, Tennessee loves to run the football. That could be an area they exploit in this game, as the Colts rank dead last in the NFL in opponent rush EPA and 30th in opponent run success rate.

Meanwhile, the Titans rank 16th and 11th in those two run defense categories, which will go a long way in slowing down Jonathan Taylor, which is the key to beating this Colts team.

I'll take Tennessee as my upset pick of the week.

Peter Dewey Week 6 Upset Pick

Carolina Panthers (-105) vs. Philadelphia Eagles

This isn’t the craziest upset pick in Week 6 – Carolina is just a 1.5-point underdog – but I can’t pass up a chance to fade this Philadelphia offense.

Saquon Barkley and DeVonta Smith are dealing with soft-tissue injuries, and the Eagles currently rank 30th in EPA/Play, 31st in success rate and 31st in yards per play this season. Only the Tennessee Titans (0-5) are averaging fewer yards per play than Philly.

I think there’s a real chance that Bryce Young and this Carolina offense (eighth in EPA/Play, sixth in EPA/Pass and fifth in yards per play) put up too many points for this Eagles team to compete. After all, the Eagles are 17th in yards per play allowed on defense and 22nd in both EPA/Play and success rate. Both of those advanced numbers are behind the Panthers’ defense this season.

If the Eagles didn’t enter the season with playoff expectations, I think they’d be underdogs on Sunday based on their statistical profile in 2026. Plus, Carolina is coming off a bye while the Eagles have a tough travel week coming from London. All signs point to a Panthers upset in Week 6.

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