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Arizona (2-0-0) at San Francisco (2-0-0)
- When: Sep 21 2025, 4:25 PM
- Where: Levi’s Stadium, Santa Clara, CA
- Where to watch: FOX
- Last Meeting: ARI 47-24, January 5th, 2025
Arizona vs San Francisco Preview & Prediction
Spread: San Francisco -2.0
Moneyline: San Francisco (-130)
Total: 45.0
Arizona Cardinals: Murray’s Dual-Threat Challenge
The Cardinals (2-0) have kicked off the season with momentum, thanks largely to Kyler Murray’s ability to improvise and extend plays. Last year, Murray tormented San Francisco, rushing for a 50-yard score in one meeting and tying his career-high with four TD passes in the other. He’s already flashed his late-game composure, closing out Carolina with a critical interception to seal the Week 2 win.
Defensively, Arizona faces a massive issue: their cornerback room is decimated. With three key players sidelined, rookies Denzel Burke and Kei’Trel Clark may see extended snaps against a 49ers offense that punishes mistakes. That could leave the door open for San Francisco’s wideouts to exploit mismatches downfield.
Player Prop Pick – Kyler Murray Over 27.5 Rushing Yards
Murray has historically hurt San Francisco with his legs, and given the pass defense concerns, scrambling could be his best weapon again.
San Francisco 49ers: QB Question Marks, Rookies Stepping Up
The 49ers (2-0) have had their share of drama at quarterback. With Brock Purdy nursing a toe injury, Mac Jones stepped in and delivered 279 yards and three touchdowns last week. Kyle Shanahan hasn’t confirmed who will start, but the offense has proven it can adapt.
The 49ers defense, meanwhile, is rounding into form. Nick Bosa and Fred Warner stressed the importance of containing Murray, and rookies like Mykel Williams and Alfred Collins showed real promise against New Orleans. If they replicate that pressure, Murray could find himself bottled up more often than last year.
Player Prop Pick – Christian McCaffrey Anytime Touchdown
With Arizona’s secondary depleted, Deebo is primed to shine as a multi-use threat in both the passing and rushing game.
Prediction & Betting Angle
San Francisco is favored by -2.0, with the total set at 45. This has the feel of a grind-it-out NFC West clash, but Arizona’s injuries in the secondary could be the deciding factor. Expect the 49ers to exploit mismatches on the outside and tighten up defensively against Murray’s scrambles.
Final Score: 49ers 24, Cardinals 20
Lean: San Francisco -2.0
Total: Under 45
- NFL Football Odds source: Bovada Sportsbook
- Get real-time live scores & latest betting odds here!
