San Francisco 49ers

San Francisco 49ers vs Arizona Cardinals Prediction, Odds and Picks for Today, 11/16/25

State Farm StadiumFOX
49ers
6-4
49ers
Today
Cardinals
3-6
Cardinals
Arizona Cardinals
Google News

49ers vs Cardinals Pickswise Expert Predictions

Point Spread Pick
ARI Cardinals Win +3.5(-110)

It’s the return of Brock Purdy here as the San Francisco 49ers get ready to take on the Arizona Cardinals. While the 49ers get their starting quarterback back the Cards can’t say the same, with Kyler Murray on injured reserve and Jacob Brissett under center for the foreseeable future. Interestingly neither team seemed to suffer much by going to their backup, and I’m going with Arizona here in large part because of that.

Mac Jones certainly didn’t seem like much of a downgrade, at least not from the Purdy we saw this year. In two games this season Purdy has thrown 4 interceptions, and it’s tough to expect him to look 100 percent here not having played since September. He’s being thrown into the fire with a division road game, and at a time when San Francisco’s defense is starting to struggle. Last week the 49ers gave up 42 to the Rams, and in their previous 2 games they gave up 24 and 26 to middling Giants and Texans offenses.

The Cardinals are coming off a rough road loss to the Seahawks, but I wouldn’t overreact too much to one game against a good team. Brissett has mostly played very well since taking over, and the Cardinals have played much better at home this year. They haven’t lost a home game all season by more than 4 points, and the game they lost by 4 was to the Packers in one where they led with less than 2 minutes to play, so I don’t get how anyone could feel comfortable laying a significant amount of points with the 49ers on the road here.

Cardinals +3.5 at publishing.

Game Totals Pick
Over 48.5(-110)

The over also makes some sense here for a few reasons. San Francisco is getting their starting quarterback back here, while Jacoby Brissett has actually looked better than Kyler Murray this year. Through 4 games as the starter, Brissett is averaging 7.2 yards per attempt with 8 touchdowns and 1 interception. Arizona just gave up 44 points to the Seahawks last week, and there have been at least 50+ points scored in 3 of their past 4.

San Francisco’s defense has also been struggling lately, and they just got shredded by the Rams last week. Los Angeles dropped 42 on them as Matthew Stafford threw for 4 touchdowns, and that was far from the only alarming performance from Robert Saleh’s defense. Just the week before they often struggled to contain the lowly and battered Giants, and the week before that they allowed CJ Stroud to have by far his most yards of the whole season as Houston scored 26 on them. Stroud threw for 318 against the 49ers, and otherwise hasn’t topped 249 this year.

Over 48.5 at publishing.

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Andrew Ortenberg

I'm an NFL handicapper here at Pickswise who was raised in a household full of sports fanatics. Since I unfortunately never had LeBron James' jumping ability I wasn't able to make it to the NBA, and chose writing about sports as the next best thing. An avid sports bettor myself, I'm excited to get to write about the industry as it gets set to take off across the country. Buckle up. For Andrew Ortenberg media enquiries, please email contact@pickswise.com.
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