Staff Predictions: Cardinals Don't Stand Chance vs Colts

The Arizona Cardinals have a tough task awaiting them in Indianapolis.

Sep 25, 2025; Glendale, Arizona, USA; Arizona Cardinals tight end Trey McBride (85) against the Seattle Seahawks at State Farm Stadium. Mandatory Credit: Mark J. Rebilas-Imagn Images | Mark J. Rebilas-Imagn Images

ARIZONA -- The Arizona Cardinals are 2-3 on the year, and many don't like their chances of reaching .500 once the dust settles against their Week 6 opponents in the Indianapolis Colts.

The Cardinals are over touchdown underdogs across many sportsbooks against Daniel Jones and the red-hot 4-1 Colts, and our weekly staff predictions are all a sweep for the home team:

Cardinals at Colts Week 6 Predictions

Oct 5, 2025; Indianapolis, Indiana, USA; Indianapolis Colts quarterback Daniel Jones (17) passes the ball against the Las Vegas Raiders during the first quarter at Lucas Oil Stadium. Mandatory Credit: Trevor Ruszkowski-Imagn Images | Trevor Ruszkowski-Imagn Images

Donnie Druin: IND 26, AZ 13

Regardless if it’s Kyler Murray or Jacoby Brissett in the mix, the Cardinals offense - in my opinion - can’t keep up in a track meet against a Colts offense that’s humming after hitting 40 points in their last two of three.

Arizona’s defense continues to hold strong but the offense continues searching for answers, and it’s tough to believe the solution arrives this week for Jonathan Gannon and co.

READ: Kyler Murray, 5 More Questionable vs Colts

Richie Bradshaw: IND 27, AZ 10

Echoing Donnie, the Cardinals are going to struggle scoring points on the road against a sneaky good Colts’ defense whether it’s Kyler Murray under center or Jacoby Brissett. If they did, they can’t outscore Indianapolis and a red-hot Daniel Jones.

Jonathan Taylor has been a man possessed running the ball this season, and he’s likely to see another heavy workload against Arizona. This could be a trap game for Indy, but Arizona is too beat up to pull it off on the road. At 2-4, the Cardinals’ 2025 season gets closer to ending playoff hopes.

Oct 5, 2025; Indianapolis, Indiana, USA; Indianapolis Colts running back Jonathan Taylor (28) celebrates after scoring a touchdown against the Las Vegas Raiders during the second half at Lucas Oil Stadium. Mandatory Credit: Trevor Ruszkowski-Imagn Images | Trevor Ruszkowski-Imagn Images

Colin McMahon: Colts 24 Cardinals 21

This matchup features two teams on two very different paths entering Week 6. Arizona is in the midst of a free fall, although all three of their losses have been by last-second field goals. I think that trend continues, or at least close to it, as I have Indy winning by just three. I think the biggest difference in this one is the coaching.

Both the Colts and the Cardinals have former Philadelphia coordinators, but I think Shane Steichen outclassed Jonathan Gannon in almost every aspect. It’ll be up to Arizona’s defense to do most of the heavy lifting again, but I just don’t see the Cardinals escaping with a win on the road.

READ: Cardinals First-Round Pick Ruled Out vs Colts

Kyler Burd: IND 27 AZ 13

The Colts have scored 33+ points three times this season while the Cardinals have maxed out at 21. The offensive woes for Arizona will likely be compounded by the absence of starting quarterback Kyler Murray.

It would be tough for me to believe that this is the week the Cardinals get back on track with Brissett manning a problematic offense on the road.