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

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.