Week 3 brings an NFC West showdown as the Arizona Cardinals travel to Levi’s Stadium to take on the San Francisco 49ers. Both teams are undefeated so far, but the 49ers enter the game with questions at quarterback and along the offensive line. Arizona’s Kyler Murray has looked sharp through two games, and if the Cardinals can pressure the 49ers’ backup QB, they have a strong chance to cover or even win outright.
Game Day Information
- Date: Sunday, September 21, 2025
- Kickoff: 1:25 PM PDT
- Location: Levi’s Stadium — Santa Clara, CA
- TV: FOX
Betting Odds & Public Betting
- Spread: Cardinals +2 / 49ers -2
- Moneyline: Cardinals +110 / 49ers -130
- Total (O/U): 45.5
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Track live public splits on the NFL Public Betting Chart
Key Notes & Storylines
- Quarterback Uncertainty for San Francisco: Brock Purdy is highly unlikely to play due to a toe injury, likely putting Mac Jones under center. Jones has potential but is inconsistent, which could open the door for an upset.
- Offensive Line Concerns: Injuries along the 49ers’ line limit protection and run-blocking effectiveness. Pressure from the Cardinals’ front seven could disrupt timing and force turnovers.
- Arizona’s Balanced Attack: Kyler Murray has been effective both through the air and on the ground. The Cardinals rely on his dual-threat capabilities to generate explosive plays.
- Defense vs. Vulnerable Offense: San Francisco’s defense remains strong, but the Cardinals have the speed and mobility to challenge them if they can win the line-of-scrimmage battle.
- Close NFC West Rivalry: Matchups between these two teams are often competitive, with games frequently decided by a touchdown or less. Execution on key drives will be decisive.
Last Three Meetings
- Nov 13, 2022: 49ers 26, Cardinals 21
- Oct 2, 2022: Cardinals 31, 49ers 28
- Nov 15, 2021: 49ers 31, Cardinals 17
The series has been tight, with the last three games separated by an average of just six points.
Cardinals vs 49ers Betting Prediction
Pick — Cardinals +2
Given the 49ers’ quarterback and offensive line uncertainties, the Cardinals have a strong chance to cover the spread. Kyler Murray’s ability to extend plays and make explosive throws gives Arizona a clear path to stay close or even steal the game. San Francisco will rely on its defense and home-field advantage, but the small spread favors the underdog if the Cardinals can pressure Mac Jones and force mistakes.
Score Prediction: Cardinals 24, 49ers 27
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