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Sep 21, 2025; Santa Clara, California, USA; Arizona Cardinals running back James Conner (6) carries the ball against the San Francisco 49ers during the second half at Levi's Stadium. Mandatory Credit: Kyle Terada-Imagn Images Kyle Terada-Imagn Images

Cardinals Lose James Conner to Season-Ending Injury

Originally posted on Arizona Cardinals on SI
By Donnie Druin | Last updated Sep 21, 2025 9:34 PM ET

The Arizona Cardinals' loss to the San Francisco 49ers and the terrible feeling around it will only last a few days before the team is forced to move on - especially with a short week on tap as the Seattle Seahawks visit in just four days for Thursday Night Football.

The absence of star running back James Conner is projected to be much longer, however.

Conner exited Week 3's loss early in the second half after a very awkward twist of his leg happened - which required the hard-nosed runner to be carted off.

ESPN Cardinals reporter Josh Weinfuss is reporting the injury could be season-ending.

"A source told ESPN that they assume James Conner's right ankle injury is severe enough to end his season but an official prognosis hasn't been made yet," Weinfuss posted on X.

A source told ESPN that they assume James Conner's right ankle injury is severe enough to end his season but an official prognosis hasn't been made yet.
— Josh Weinfuss (@joshweinfuss) September 22, 2025

ESPN NFL insider Adam Schefter doubled down in another post saying, "Cardinals RB James Conner did in fact suffer a season-ending injury to his right ankle that will require surgery, per source. The injury is considered 'severe', even if the team does not yet know the full extent of the damage."

Conner, Arizona's bellcow rusher, was a big part of the Cardinals' weekly gameplans in a Drew Petzing offense that is predicated (and heavily reliant) on finding success on the ground.

Conner, who earned a nice contract extension with the team following consecutive 1,000-yard rushing campaigns, again was set to play a big role in the desert.

Also playing the role as a team captain, Arizona lost more than just one of the league's toughest runners - they also lost part of their mojo.

"I feel like the guys were sensitive when he went down because he's the heart and soul of our team, I feel like," linebacker Mack Wilson Sr. said after the game (h/t AZCardinals,com).

Quarterback Kyler Murray added, "That's so unfortunate. Not only is he my teammate, I feel like that's a brother of mine. Just seeing him go down like that - you never want to see that.

"I understand it's part of the game but it's not ideal. All the work that he puts in and just who he is as a person, you don't want to see him get hurt like that. It's tough."

The Cardinals now will pivot to Trey Benson as their RB1 - who was drafted before last season as the second running back taken at his position.

Benson has flashed the ability to hit home runs at the next level, and now will need to make the next jump whether he's ready or not.

"I'm gonna do it for him. He's gonna be my motivation for the rest of the year and I can't wait," Benson told reporters following the game.

We're set to speak with Cardinals head coach Jonathan Gannon on Monday afternoon, so perhaps we'll receive an official update then.

However, all indications are Conner is done for the year.