Arizona Cardinals (2-0) at San Francisco 49ers (2-0) Preview, Prediction & Odds | Week 3, 2025

Something has to give. When the Arizona Cardinals (2-0) travel to Levi’s Stadium to take on the San Francisco 49ers (2-0) this Sunday, one team will walk away with its first loss of the season. Both NFC West powerhouses have scraped by with narrow victories to remain undefeated, setting the stage for a high-stakes divisional showdown.

The Cardinals are coming off a tight home win against the Carolina Panthers, while the 49ers’ defense secured a game-winning play to hold off the New Orleans Saints. Both squads are battling early-season injuries, but with the NFC West lead on the line, neither will be looking for excuses. 

Betting Odds

** Odds Subject to Change – Courtesy of ESPN

Tale of The Tape

Key Details

Arizona Cardinals

The Arizona Cardinals have built their identity on a powerful running game, but it has yet to fully ignite this season. While they rank a respectable 13th in the league in rushing yards per game, the numbers are inflated by a couple of long runs, including a 31-yard scramble by quarterback Kyler Murray. Running back James Conner, the team’s emotional leader, has been held to just 73 yards on 23 carries through two games. Despite the slow start, there’s a strong belief within the organization that they are on the verge of a breakout.

Last season, Conner was a force against the 49ers, racking up 34 rushing yards on the game-winning drive alone in their 24-23 victory. For the Cardinals to replicate that success, they’ll need to establish the run early and control the line of scrimmage. The mobility of Murray also poses a significant threat. He has a history of torching the 49ers with his legs, and his ability to extend plays could be the key to neutralizing San Francisco’s aggressive pass rush. If the Cardinals can get Conner loose and allow Murray to create on the run, their offense will be tough to stop.

San Francisco 49ers

The San Francisco 49ers have been a testament to resilience, winning their first two games despite a growing list of injuries. With starting quarterback Brock Purdy’s status in doubt (as of Sept 18), there is confidence in Mac Jones if he has to play again. Jones has shown poise under pressure, leading a crucial touchdown drive before halftime against the Saints.  

The injuries extend beyond the quarterback position. With star receiver Brandon Aiyuk out, rookie Ricky Pearsall has become the top target, hauling in eight catches for 164 yards over two games. Pearsall found the end zone against the Cardinals last season and will be looking to do so again. On defense, the 49ers have leaned on their depth, with rookies like defensive lineman Mykel Williams making a noticeable impact. Even with key players missing, Shanahan’s squad has found ways to win, and they’ll rely on that “next man up” mentality to try and contain a dynamic Cardinals offense.

Prediction

Purdy will play, and the 49ers will win.

Final Pick

San Francisco 49ers  -2.5