Arizona Cardinals vs San Francisco 49ers
An NFC West showdown takes place in the desert on Sunday between the Cardinals and 49ers.
San Francisco may be getting its starting quarterback back on the field, along with one of its top receiving threats, when it travels to Arizona.
Cardinals backup quarterback Jacoby Brissett remains under center, but he’ll be without his top weapon, Marvin Harrison Jr., who underwent appendicitis surgery this week.
How will these changes impact Sunday’s matchup? I’ll break it all down with my Arizona Cardinals vs. San Francisco 49ers preview and picks.
For additional information on picks, props, moneylines, and more on today’s slate, take a look at our NFL Picks Page or our NFL Odds Page.
You can also browse our recommendations for the best online sportsbooks available in the U.S.
Arizona Cardinals vs San Francisco 49ers NFL Betting Insights
Can Jacoby Brissett get the Cardinals back in the win column this weekend?
Cardinals vs 49ers Preview
Reports out of practice this week are hinting at a possible return for Brock Purdy, who hasn’t played since Week 4 due to a toe injury. In the meantime, Mac Jones has filled in, leading San Francisco to a 5-3 record in his starts while ranking second in the NFL in passing yards per game (268.9) and ninth in completion percentage (69.6%).
Based on the early portion of 49ers practice, it indeed looks as if the 49ers are preparing Brock Purdy to return to his starting role Sunday at the Cardinals.
— Matt Maiocco (@MaioccoNBCS) November 12, 2025
Coach Kyle Shanahan has made it clear that if Purdy is good to go, he’ll be the starter. I don’t view much difference between Purdy and Jones. In this system, Shanahan and the surrounding weapons are the reason for the success, so the offense shouldn’t look much different regardless of who’s under center.
Whoever it ends up being will face a Cardinals defense that ranks 28th in success rate and 15th in EPA per play allowed. Arizona has struggled against the pass, sitting 25th in dropback success rate and 18th in dropback EPA. Overall, the Cardinals are giving up 24 points per game (19th), but that number has climbed to 29.3 over their last three contests.
Aside from getting their starting quarterback back, things are also trending up for wide receiver Ricky Pearsall’s status on Sunday. Pearsall makes an immediate impact when active. Through four games, he’s totaled 20 receptions on 29 targets for 327 yards (16.4 yards per catch).
On the other side, Jacoby Brissett will be making his fifth start of the season. He’s completed 61% of his passes for just over 1,100 yards with eight touchdowns and only one interception. He’s been serviceable and can be more than that against a 49ers defense nowhere close to what it was in years past. This season, under defensive coordinator Robert Saleh, San Francisco ranks 30th in success rate and 26th in EPA/play allowed. They’re giving up 5.5 yards per play (21st), and even more over their last three games (5.9).
Since Week 6, with Brissett under center, the Cardinals offense ranks 18th in both EPA/play and success rate, so perhaps Arizona can hang around despite their defensive issues.
Arizona vs. San Francisco Picks
What really stood out last week wasn’t just how badly the Cardinals were beaten by the Seahawks—44-22—but that the score got that high with Sam Darnold only completing 10 of 12 passes for 178 yards, one touchdown and one pick.
Plain and simple, the Cardinals are not a good football team. Brissett is fine, but he won’t be able to do enough to keep pace with what the 49ers should be able to do against Arizona’s weakened defense.
This is a big spot for San Francisco—not only because they’re getting key players back, but because they need to start making a playoff push before it’s too late.
Look for the 49ers defense to hold things together well enough, and for Shanahan to scheme up enough offense to win and cover.
I am going to pay a bit more to get under the key number of -3. Laying -124 to get the 49ers at -2.5 is available, and that’s what I’m rolling with.
NFL Record: 59-46 (+5.23 units)
Still Didn’t Get Your NFL Fix?
Follow me on X @dannyburke5 for all my picks, analysis and plenty more. Also be sure to follow Betting News on ‘X’ and Twitch to catch us on stream! Betting News is also on TikTok! Follow us for more picks and news every day and check out our Free Expert Picks for every major sports league.
More NFL News
NFL Betting News
Dallas Cowboys vs Minnesota Vikings Preview & Predictions (12/14)
NFL Betting News
Chasing Six | NFL Week 15 Anytime Touchdown Bets
Get FREE Picks and Props Weekly
Sign up for
THE WEEKENDER NEWSLETTER