The Colts’ Week 6 opponent is dealing with an injury to a key starter that could play a large factor in their upcoming matchup

The Colts have to prepare for two different QBs they could potentially face in Week 6

Destin Adams NFL News Writer
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Colts head coach Shane Steichen
Marc Lebryk-Imagn Images

Next up on the red-hot 4-1 Indianapolis Colts’ schedule is the 2-3 Arizona Cardinals. These are two teams that don’t meet often in the regular season.

The last matchup between these teams occurred in December 2021. To say that these teams don’t know each other well would be an understatement. This matchup might get shaken up further with a key Cardinals starter missing practice on Wednesday due to an injury.

Kyler Murray’s career stats vs. the Colts

  • 0-1 (22-16 Colts Win 12/25/2021)
  • 27/43 (62.8%) for 245 yards
  • One touchdown, zero interceptions, two fumbles (zero lost)

Cardinals QB Kyler Murray is dealing with an injury ahead of the Week 6 matchup vs. the Colts

Cardinals QB Kyler Murray
Oct 5, 2025; Glendale, Arizona, USA; Arizona Cardinals quarterback Kyler Murray (1) warms up before their game against the Tennessee Titans at State Farm Stadium.

Cardinals QB Kyler Murray was held out of practice on Wednesday due to a foot injury. Murray left the team’s Week 5 matchup against the Tennessee Titans early but returned. Unfortunately, it didn’t matter as the Cardinals blew a big lead and lost to a Titans team that hadn’t won a game up to that point. These Cardinals are probably feeling similar to how the Colts felt after their loss to the Los Angeles Rams. Both teams had an embarrassing fumble at the one-yard line that negated a touchdown, but the Cardinals also had other off-the-wall things happen due to their own mistakes.

After the Colts’ loss, they came out and dominated the Las Vegas Raiders. The Colts will be looking to prevent the Cardinals from having a similar bounce-back performance. Indianapolis can improve to 5-1 ahead of its road trip to California to take on the 3-2 Los Angeles Chargers. Some may view Murray as a non-significant loss if he can’t play due to his recent struggles. I completely disagree with that notion, for multiple reasons.

Anytime a team has to adjust to playing without its starting QB, it’s a significant change to its weekly game plan. Secondly, the Colts’ defense has struggled to corral quarterbacks who can run. In Week 2 vs. Bo Nix, that was put on full display, as Nix picked up multiple key first downs with his legs.

Murray is an even greater threat with his legs, and I could see him giving the Colts trouble. If he can’t play, expect former Colts QB Jacoby Brissett to get the start.