Arizona Cardinals vs. San Francisco 49ers Picks and Prediction for Sunday, September 21, 2025
Use Code WWWC Arizona Cardinals (2-0) vs. San Francisco 49ers (2-0)
The Arizona Cardinals (2-0; 1-1 ATS; 1-1 O/U) head to Levi’s Stadium in Santa Clara, CA, on Sunday afternoon to face off against the San Francisco 49ers (2-0; 2-0 ATS; 1-1 O/U) in the NFC West showdown, so here’s our Cardinals vs. 49ers prediction along with the team stats, news, and latest odds update.
Arizona and San Francisco lock horns for the first time this season. The Cardinals went 2-0 SU and ATS against the 49ers last season, beating San Francisco 47-24 at home and 24-23 at Levi’s Stadium.
Let’s take a closer look at this Cardinals vs. 49ers prediction, one of our NFL picks for Week 3. The 49ers are 2.5-point home favorites with a total of 44.5 points.
The Cardinals survived a scare in Week 2
The Arizona Cardinals outlasted the Carolina Panthers 27-22 last Sunday, failing to cover a 7-point spread in front of the home audience. The Cardinals nearly blew a 24-point lead, and Carolina outscored Arizona 13-0 in the fourth quarter.
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The Panthers made it a five-point game with 1:58 left in the quarter. Then, they converted an onside kick, but the Panthers’ ultimate drive was unsuccessful, as Bryce Young was sacked on fourth down with 26 remaining on the clock.
The Cardinals racked up 293 total yards in Week 2. They rushed 22 times for 82 yards, while Kyler Murray threw for 220 yards, a touchdown, and an interception. Trey McBride had six receptions for 78 yards, and James Connor carried the pigskin 11 times for 34 yards and a touchdown.
“Ultimately, we made enough plays to win the game,” Arizona coach Jonathan Gannon said. “I obviously have to do a much better job making our guys, all three phases, understand how to close games out. I've got a lot of work to do.”
Back in Week 1, the Cardinals beat the New Orleans Saints 20-13 as 5.5-point road favorites. The Saints had a chance to tie the game, but the Cardinals managed to defend the end zone as the time expired. Murray threw for 163 yards and two touchdowns, while Marvin Harrison Jr. had five catches for 71 yards and a TD.
The Cardinals lost a couple of guys in Week 2. Cornerback Garrett Williams and defensive end L.J. Collier both suffered knee injuries and will miss some time.
The 49ers emerged victorious in Mac Jones’ debut
The San Francisco 49ers are coming off a 26-21 road victory against the New Orleans Saints in Week 2. With Brock Purdy on the shelf due to a shoulder injury, Mac Jones got the starting call and threw for 279 yards and three touchdowns.
The 49ers outgained the Saints 344-307 in total yards. San Francisco gained just 77 yards on the ground, but Jones was terrific in his 49ers debut. Christian McCaffrey had six receptions for 52 yards and a touchdown and 13 carries for 55 yards, while Jauan Jennings caught five of his 10 targets for 89 yards and a TD.
“I’ve worked a lot on my mindset this offseason,” Mac Jones said. “The line did a great job blocking for me, and when they do that, I know I can sit in there and let it fly. It’s good to feel a little bit of confidence again, and I just have to carry that to next week.”
The Niners started their 2025 campaign with a 17-13 road victory over the Seattle Seahawks. Brock Purdy threw for 277 yards and a couple of touchdowns and interceptions, while Ricky Pearsall posted four receptions for 108 yards. The 49ers outgained the Seahawks 384-230 in total yards.
San Francisco lost George Kittle in Week 1, and one of the best tight ends in the league landed on the IR with a hamstring injury. Guard Ben Bartch is on the IR, too. Fullback Kyle Juszczyk suffered a concussion last week, while Jauan Jennings is questionable for the Cardinals game due to an ankle injury. Purdy did participate on a limited basis on Wednesday, but Jones will most liklely get the call again this week at quarterback.
Cardinals vs. 49ers Pick
Spread Pick for Cardinals vs. 49ers
- Arizona Cardinals +2.5 (5 units)
The 49ers are 2.5-point favorites because of their defense. San Francisco has only allowed 537 total yards through the first two weeks of the season. That’s 130 fewer yards than Arizona has allowed, but the Cardinals don’t look like a bad defensive team.
The Cardinals surrender just 78.0 rushing yards per game (6th in the NFL). The 49ers’ ground game hasn’t impressed, even with Christian McCaffrey on the field, and I think that Arizona will find a way to keep it close in this matchup. Kyler Murray can lean on Trey McBride and Marvin Harrison Jr. to hurt the sturdy Niners secondary.
Arizona is 9-4 ATS in its last 13 games overall and 6-3 ATS in its previous nine contests played in September. On the other side, San Francisco is 3-8 ATS in its last 11 games overall and 4-12 ATS in its previous 16 outings at home.
Over/Under Pick for Cardinals vs. 49ers
- Over 44.5 (5 units)
Arizona and San Francisco will find a way to move the chains against each other. The Cardinals are building up their form, and I mentioned that they have a couple of top-notch playmakers in Trey McBride and Marvin Harrison Jr.
The 49ers miss George Kittle, whose absence is a massive blow to San Francisco’s offense. They also lack explosion at wide receiver with Brandon Aiyuk out for another few games due to a knee injury. Yet, the Niners have enough weapons to hurt the Cardinals, whose passing defense has flaws. Arizona just allowed Bryce Young to throw for three touchdowns.
The over is 5-2 in Arizona’s last seven games overall, and it is 4-1 in San Francisco’s previous five. Also, six of their last seven head-to-head duels have gone over the total.
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