San Francisco 49ers vs Arizona Cardinals Picks and Predictions September 21st 2025

San Francisco 49ers vs Arizona Cardinals September 21st 2025

In Week 3 of the 2025 NFL season, the Arizona Cardinals will visit the San Francisco 49ers at Levi’s Stadium. Both teams have started the season strong with a 2-0 record. The game will take place on Sunday, September 21, 2025, at 4:25 PM and will be broadcast on FOX. The weather forecast predicts a mild day with clear skies, making for ideal playing conditions.

The Cardinals, led by head coach Jonathan Gannon, have shown solid performance both at home and on the road. Meanwhile, the 49ers, under the guidance of head coach Kyle Shanahan, have also been impressive, especially in their division games. This NFC West showdown promises to be an exciting contest as both teams aim to maintain their unbeaten streaks.

Cardinals vs 49ers Key Information

• Sport: NFL Football
• Teams: Arizona Cardinals vs. San Francisco 49ers
• Venue: Levi’s Stadium in Santa Clara, CA USA
• Date: Sunday, September 21, 2025
• Betting Odds: Cardinals Moneyline +107, 49ers Moneyline -127, Cardinals Spread +1.5 (-109), 49ers Spread -1.5 (-111), Total Over 44.5 (-108), Total Under 44.5 (-111)

The San Francisco 49ers and the Arizona Cardinals meet on Sunday in Santa Clara with both teams entering unbeaten at 2-0. Each has relied on clutch defensive stops in the final minutes to secure victories, but now they’ll battle for early control of the NFC West, the only division with multiple undefeated teams. Both clubs understand their margin for error has been slim, but both also bring confidence into this key divisional clash.

Betting Odds

The San Francisco 49ers Can Win If…

The 49ers have leaned on their defensive playmaking to close out games, including strip sacks in the final minutes of each of their first two wins. Nick Bosa, who continues to anchor the defensive front, sets the tone with relentless pressure. Alongside Fred Warner, who earned NFC Defensive Player of the Week honors with 11 tackles, a forced fumble, and a recovery, this unit is capable of turning tight contests into victories late.

Quarterback health is an important factor. Brock Purdy missed last week’s win over New Orleans with turf toe, leaving Mac Jones to step in with 279 yards and three touchdowns. If Purdy returns, his chemistry with receivers and efficiency in Kyle Shanahan’s system could help stabilize the passing attack. Regardless of who starts, San Francisco’s eighth-ranked total offense has the ability to move the ball consistently.

Christian McCaffrey’s production has yet to break loose, with only 124 rushing yards through two games at a 3.5-yard average. However, his presence as a dual threat remains crucial, especially in the passing game where he’s added 15 receptions for 125 yards and a touchdown. If the offensive line, despite injuries, can open lanes, McCaffrey’s breakout game could arrive at just the right time.

The Arizona Cardinals Can Win If…

The Cardinals have thrived on late-game defensive stands, surviving by slim margins against the Saints and Panthers. Kyler Murray remains the X-factor, capable of extending plays and generating offense even when the scheme falters. His dual-threat ability helped the Cardinals upset San Francisco on the road last season, and his improvisation will once again be central to Arizona’s hopes.

Arizona’s defense must step up against a San Francisco team that can attack in multiple ways. Injuries at cornerback have left the secondary thin, with Garrett Williams placed on injured reserve and both Max Milton and Will Johnson banged up. Denzel Burke and Kei’Trel Clark will likely see extended snaps, making it vital for the Cardinals’ pass rush to collapse the pocket and prevent big plays.

Offensively, the Cardinals are ranked just 24th in total offense and 27th in passing, which limits their margin for error. However, they’ve been disciplined with ball security and will need to continue avoiding turnovers to give themselves a chance. A grind-it-out game plan with careful clock management could keep Murray in striking distance late.

The Lean

San Francisco enters as a 6.5-point favorite at home, and the model projects them to win by a score of 27-17. The 49ers’ defense is likely to be the difference against an Arizona team that struggles to generate passing yards. With Purdy trending toward a return, San Francisco has the edge in offensive balance. The recommendation is to take the 49ers -6.5.

The total for the game is 44.5. While both teams have had late-game drama, their defensive strengths suggest a lower-scoring contest. San Francisco has yet to score more than 28 points, and Arizona’s offense has not proven explosive. The lean is on the under 44.5, with the expectation that both defenses keep scoring in check.

Projected Score & Matchup Stats

Game Preview Recap

This NFC West showdown matches two unbeaten teams who have both relied heavily on defense in the early going. San Francisco’s defensive front has delivered in crunch time, while Arizona has held its ground inside the red zone during late-game drives. The matchup carries weight as early momentum in the division could set the tone for playoff positioning.

The recent history between the teams shows balance, with each side winning five of the past 10 meetings. Arizona has proven capable in Santa Clara, winning three of the last five trips, including a 24-23 victory last October behind Murray’s dual-threat performance. Shanahan and his defense will look to prevent a repeat of that scenario.

Injuries could play a factor, with San Francisco missing George Kittle again and dealing with issues across the offensive line. The Cardinals are thin in the secondary, which may expose them to big plays if Purdy returns. Both coaches acknowledge the need to improve execution before more difficult stretches of the schedule arrive.

With both teams 2-0, the outcome may hinge on quarterback play. Murray’s ability to improvise and Purdy’s potential return from injury provide intrigue, but San Francisco’s defensive edge and home field give the 49ers the upper hand heading into Sunday.