Reasons Why Cardinals Will Win, Lose vs Colts

After three straight last-minute losses, the Arizona Cardinals shift their focus toward a road trip to the Midwest, as they'll take on the Indianapolis Colts in a Week 6 battle between two teams going in polar opposite directions.

For the Cardinals, they’re looking to get back to .500 following three games that they’d like to forget. Incredibly frustrating starts against San Francisco and Seattle, followed by a heartbreaking yet embarrassing finish against Tennessee, have dwindled hope from the fan base, but a win could get Arizona back on track.

The Indianapolis Colts, however, are a red-hot 4-1 and have a serious argument to be the NFL’s best team through five weeks. Quarterback Daniel Jones has this team playing at a high level, while running back Jonathan Taylor looks like a possible Offensive Player of the Year candidate.

With two teams seemingly on opposite sides of the spectrum set to clash on Sunday, the Cardinals will have to be at their best. This is a winnable game, though, as if Arizona does what it’s capable of, it’s not unfeasible for the Cardinals to pull off the upset in Indy.

With that, here are four critical facets of the game that will contribute toward either a win or a loss for Arizona against the Colts.

LOSS: Offense continues previous trend of slow starts

Against the Titans, the Cardinals scored a touchdown on three of their first four drives, but in the previous two games, the offense was nowhere to be found to begin the game.

Because of an incredibly poor finish against Tennessee, it’s reasonable to assume that the offense might pick up where it left off, and by that, I mean not scoring many, if any, points.

Kyler Murray hasn’t been great in stretches, and while he was phenomenal in the first quarter of the Titans matchup, he can’t afford to come back to earth when the first quarter against the Colts rolls around. He and the offense will need to hit the ground running, and a slow start would doom Arizona.

The Colts run the ball exceptionally well, which gives them a significant advantage when they get a lead. This means that the Cardinals need to have a solid start, and a stagnant offense to begin the game would pretty much kill all hope of an early lead.

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WIN: An effective run game that includes Murray

Arizona Cardinals quarterback Kyler Murray (1) scrambles for a first down as Tennessee Titans linebacker Cody Barton (50) closes in at State Farm Stadium in Glendale on Oct. 5, 2025. | Joe Rondone/The Republic / USA TODAY NETWORK via Imagn Images

On the flip side, if the Cardinals want to get ahead early through a cohesive offense, they’ll need to establish some kind of run game. With a trio of backs including Michael Carter, Emari Demercado and Bam Knight, Arizona has several options through the run game, but it should also utilize Murray’s legs as well.

When Murray is creating plays outside of the pocket, that’s when he’s at his best. It might not look pretty at times, but Murray can make plays very few other quarterbacks can. If both he and the running backs can set the tone, the Cardinals’ offense will be able to flourish.

When a defense has to adjust for the run, then the pass game will follow, and with Murray involved in both components, the Colts’ defense will have to choose to defend one or the other.

An effective offense all starts with the run, and if the Cardinals can find that, especially early on, they should have a good shot at scoring enough to secure a huge road victory in Indianapolis.

LOSS: Allow Jones to make big plays with his arm

I’ve mentioned that Taylor and the Colts’ run game have been fantastic, but in what might be the biggest surprise of the season thus far, Jones has been a superb quarterback in almost every way.

He’s been solid with short passes, but he’s also been accurate going deep as well. With threats like Michael Pittman Jr., Alec Pierce and A.D. Mitchell, Jones has been able to stretch his offense out, which just allows for a more dominant run game when the defense has to adjust for the air threat.

If the Cardinals allow Taylor to run wild and that’s all the offense the Colts get, so be it, but they can’t let Indianapolis become multifaceted when they have the ball. The easiest way to do that is to take away the vertical passing threat.

If Jones is able to stretch the field and make highlight-reel plays with his arm, you can pretty much consider this game over, as with a rock-solid run game, there will be no stopping the Colts’ offense at that point.

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WIN: Stay composed for all 60 minutes

This is a bit of a generality, but with the Cardinals through five weeks, it has to be said. They’ve struggled mightily to put together a complete performance, and you could make a strong argument that they still have yet to do so despite two wins on their résumé.

In all five games, Arizona has either lost focus toward the end of the game or not come out prepared. Against a 4-1 squad, this simply can’t happen. The Cardinals don’t need to play flawless football for the entire game, but they need to avoid those stretches where the other team possesses all the momentum.

A lot of this has to do with coaching, and there’s been a lot of talk about the future of the coaching staff, but as for the here and now against the Colts, everyone needs to get it together.

It starts with Jonathan Gannon, but it’s on everyone in the organization to finally piece together a full 60 minutes of sound football. This is a must if Arizona wants to escape with a win, and it might not seem like a tall task, but it’s painfully obvious that the Cardinals need to stay calm and collected from start to finish.