Arizona Cardinals vs Indianapolis Colts Prediction, Odds and Picks for Sunday, 10/12/25

One of the more fascinating games on the NFL Week 6 card comes in Indianapolis, where the red-hot Colts are set to take on the Arizona Cardinals in a game between a pair of teams that are coming off very different results a week ago. Indianapolis looks like a clear playoff team at the moment, with the Colts tied atop the AFC South with Jacksonville and taking care of business each week, with the exception of a close loss on the road against the Rams. On the other side, the Cardinals blew a 21-6 lead in the 4th quarter at home against the lowly Tennessee Titans, a performance highlighted by running back Emari Demercado dropping the ball at the goal prior to scoring what would’ve been a 72-yard touchdown to essentially clinch the game. To make matters worse, the Cardinals also saw quarterback Murray suffer a foot injury last Sunday during the collapse, a play that saw him miss a few snaps before finishing the game. Murray is currently listed as questionable for Sunday’s game, but he did return to practice on Friday, which is obviously an encouraging sign.

I’m immediately drawn toward backing the Cardinals this week, especially since nobody is going to want to bet on Arizona following that debacle of a 4th quarter a week ago. Even if Murray doesn’t end up suiting up on Sunday, this number is pretty disrespectful to a Cardinals team that has lost a trio of games by a combined 5 points over the past 3 weeks. Arizona has actually led in the 4th quarter of each contest, which also points me in the direction of Jonathan Gannon’s team catching over a touchdown in this one. We can expect this game to be close — much like every game involving the Cardinals to this point. And while Daniel Jones and the Colts are undoubtedly one of the surprises of the year thus far, Indianapolis is getting a bit too much respect in the market for my liking here. Let’s hold our noses and take Arizona to keep it close.

Cardinals vs Colts prediction: Cardinals +7.5 available at time of publishing. Playable to 7.

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Regardless of which teams ends up winning and/or covering the spread on Sunday, the under pairs nicely with both outcomes. You wouldn’t ordinarily think it with these teams, but both sides are actually quite solid defensively. The Colts are 5th in EPA per play on defense through five weeks, while also checking inside the top 10 in EPA per pass. Indianapolis has a harder time stopping the run, but that is likely not going to be as much of a problem in this game given the Cardinals’ injuries at the running back position. On the other side of the ball, Arizona is 12th in EPA per play and a top 5 rush defense per a number of metrics, which is imperative against a Colts offense that has been excellent on the ground to this point. This is a game that should be played in the mid 20s, so I’d play this number down to 47.

Under 47.5 available at time of publishing. Playable to 47.