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Sep 7, 2025; New Orleans, Louisiana, USA; Arizona Cardinals head coach Jonathan Gannon looks on against the New Orleans Saints at Caesars Superdome. Mandatory Credit: Stephen Lew-Imagn Images Stephen Lew-Imagn Images

Gameplan: How Cardinals Can Upset 49ers

Originally posted on Arizona Cardinals on SI
By Richie Bradshaw | Last updated Sep 21, 2025 2:00 PM ET

One of the most volatile rivalries in the NFC West starts the season in Santa Clara, with the Arizona Cardinals visiting the San Francisco 49ers.

Both of these teams are off to 2-0 starts, but they've also been marred by critical injuries. The stakes for this game are raised because of that, as having an early-season win while not at 100% health-wise will matter more the next time these two teams meet.

For the Cardinals to leave the Bay Area with a big win in the division and move to 3-0, they need to play the 49ers as if they're still playing completely healthy. They may be missing some of their best players like George Kittle, but they haven't lost others (more on some of them later).

San Francisco remains well-coached under Kyle Shanahan, as well, so this game is no guarantee, especially as we wait to see how Arizona manages its own injuries.

I have constructed the perfect winning formula for the Cardinals. By accomplishing these three tasks, I can assure victory for the team and its first 3-0 start since 2021:

Wake up the run game

The calling card for the Cardinals was supposed to be the run game this year, but it's been widely nonexistent thus far. The team has been able to do just enough everywhere else, but they're still struggling to run the offense efficiently. If that doesn't change soon, the season will get out of hand.

San Francisco is right in the middle of the pack in terms of run defense, so Arizona has a chance to get things on track. Arizona can dictate the pace of the game by effectively running the football in this game, and a banged-up 49ers'= offense could struggle to keep up.

Game plan for Nick Bosa/Fred Warner

Although the 49ers' offense is working through major injuries, its defense has its two best players ready to go. Bosa and Warner remain near the top of their respective positions as the best of the best. They're no stranger to wrecking game plans, and they alone can hand the Cardinals a loss.

Unfortunately, when it comes to these two, it's all about containment because you won't stop or neutralize them. The Cardinals have to make sure they can exploit the other nine players on defense and generate success away from #97 and #54.

Shrink opportunities for Mac Jones

Jones looked exceptional last week for the 49ers in relief of the injured Brock Purdy, but that's not hard to do against a bad Saints team with Kyle Shanahan making the game script easy to follow. We've seen peaks and valleys from Jones in his pro career, and the Cardinals have more than enough tape to find his tendencies even with a new team.

The biggest key to this game will be for the Cardinals to make sure Jones never gets comfortable in any way, shape, or form. Jones can't be in a rhythm as a passer or comfortable handing off the ball, and the Cardinals can do that by taking away the easy decisions. By shrinking the "gimme" plays, Jones could be forced to make decisions he shouldn't, and even a banged-up Cardinals defense can capitalize on that.