Arizona Cardinals vs San Francisco 49ers Prediction, Odds and Picks for Today, 09/21/25

NFC West action here in Week 3 as the San Francisco 49ers get ready to host the Arizona Cardinals. Kyle Shanahan said the other day that Brock Purdy is very unlikely to play, so it looks like it’ll be the second game of the Mac Jones experience for the 49ers. The first game ended in a victory, but I’m skeptical Jones will be able to make it two in a row here. For starters, the victory came against a Saints team that might be the worst in the league, and it wasn’t all that convincing.

San Francisco won by 5 points, and New Orleans had the ball driving with a chance to take the lead with a minute to play before getting stopped on a 4th and 1. This is a much tougher test here against a Cardinals team that has quietly started 2-0. Last week’s 27-22 win over the Panthers wasn’t nearly as close as that final score suggests, as Arizona got out to a 27-3 lead and controlled the game from start to finish.

Kyler Murray and Trey McBride have picked up right where they left off last year, and I think they should have some success here against a 49ers defense that lost some key guys this offseason. Last year the Cards beat the 49ers twice, and while Purdy didn’t play in the second matchup he did play in the first. Jones playing for Shanahan is a fun story, but this is a guy who averaged 6.4 yards per attempt with as many interceptions as touchdowns during his half-season stint starting for the Jaguars last season.

Cardinals vs 49ers prediction: Cardinals +2.5 available at publishing. Playable to +2

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I also think the under makes some sense here. It’s true that neither defense has been tested yet as they’ve both already had the luxury of facing Spencer Rattler, but I don’t see either offense being explosive here. Mac Jones has been downright terrible with the Jaguars and Patriots the last few years, and I don’t think he’s going to magically change the quarterback he is just by playing for Kyle Shanahan. He was facing a terrible Saints defense last week, and will face a much tougher test against a Jonathan Gannon defense that just embarrassed Bryce Young for three quarters last week.

In Week 1 when the 49ers had Purdy the entire game, they only managed to muster 17 points against the Seahawks. Christian McCaffrey has been bottled up through two games, and the Cardinals don’t have many reliable weapons outside of Trey McBride as Kyler Murray and Marvin Harrison Jr still don’t appear to be on the same page. This is a pivotal division game between two 2-0 opponents, and I think points will be at a premium.

Under 45.5 available at time of publishing. Playable to 45.