Why Did Cardinals Lose to 49ers? 3 Key Factors

These are the reasons why the Arizona Cardinals couldn't bring home the win.

Sep 21, 2025; Santa Clara, California, USA; Arizona Cardinals quarterback Kyler Murray (1) is pressured by San Francisco 49ers defensive end Mykel Williams (98) during the second half at Levi's Stadium. Mandatory Credit: Cary Edmondson-Imagn Images | Cary Edmondson-Imagn Images

Well, that was an interesting game.

The Arizona Cardinals came up just short in the end on the road against the San Francisco 49ers (you can check out our recap here). There were some positives, but also plenty of negatives - though the injury bug certainly hasn’t been helping them either.

Let’s take a closer look at some of the key factors that led to the Cardinals’ loss to the 49ers today. 

Run Game Struggles

Sep 21, 2025; Santa Clara, California, USA; Arizona Cardinals running back Trey Benson (33) carries the ball as San Francisco 49ers safety Jason Pinnock (25) defends during the second half at Levi's Stadium. Mandatory Credit: Cary Edmondson-Imagn Images | Cary Edmondson-Imagn Images

It certainly didn’t help James Conner was carted off the field to begin the second half. But even with him in the game, the Cardinals could barely get the ball moving on the ground, finishing with just 106 yards.

Through the first three weeks of the season, the Cardinals rank in the bottom half of the league offensively. They average just 114 yards per game on the ground, which ranks 24th in the league overall. Conner is one of the biggest pieces of this offense.

If the Cardinals end up losing him for a while, that would really be a tough hit for them. 

READ MORE: Jonathan Gannon Takes Blame for Struggles

Lack of Marvin Harrison Jr.

Sep 21, 2025; Santa Clara, California, USA; Arizona Cardinals wide receiver Marvin Harrison Jr. (18) is unable to come up the catch as San Francisco 49ers cornerback Renardo Green (0) defends during the first half at Levi's Stadium. Mandatory Credit: Cary Edmondson-Imagn Images | Cary Edmondson-Imagn Images

The Cardinals have talent on the offensive side of the ball. It’s just confusing sometimes as to why they don’t use them enough, especially with guys like Marvin Harrison Jr. in the mix.

He isn’t off to the hottest start in the 2025 season, but a lot of that also is not his fault. The Cardinals really need to find a way to get him more involved on the offense. 

Cardinals Secondary

Sep 21, 2025; Santa Clara, California, USA; San Francisco 49ers wide receiver Ricky Pearsall (1) makes the catch inform of Arizona Cardinals safety Jalen Thompson (34) during the second half at Levi's Stadium. Mandatory Credit: Cary Edmondson-Imagn Images | Cary Edmondson-Imagn Images

The Cardinals' secondary might be a problem, and not in a good way. Simply put, they have been getting lucky these past few weeks.

Arizona barely beat the Saints in Week 1 before almost blowing it against the Panthers last week. The Cardinals need more playmakers on the defensive side. They have the money to make a move. This should be a year to make that big move for a playoff push.

Overall, it was a tough loss with the Cardinals. Mack Wilson Sr. was the star of the show today for the Cardinals, finishing with 12 total tackles and two pass deflections.

There is still a lot of season left, but something needs to change. They need to use Harrison more. They need to trade for a corner. The Cardinals have always done well getting multiple guys involved in the passing game, but they've yet to show that so far.