Arizona Cardinals vs San Francisco 49ers Prediction, 9/21/2025 NFL Picks, Best Bets & Odds Week 3

Game: Arizona Cardinals vs San Francisco 49ers

Date: Sunday, September 21, 2025

Location: Levi's Stadium in Santa Clara, CA

TV: FOX

Odds-Point Spread: 49ers (-1.5)

Total-Over-Under: 43.5

Levi's Stadium is the place where the San Francisco 49ers (2-0) will attempt to beat the Arizona Cardinals (2-0) on Sunday. Arizona opens this game as 1.5-point underdogs from oddsmakers. The total is set at 43.5.

The Arizona Cardinals step on the gridiron holding a record of 2-0 for the year. When they last took the field, the Cardinals faced the Carolina Panthers and walked away with a win by a score of 27-22. James Conner led the offense in rushing for the Cardinals with 11 attempts for 34 yds (3.1 yards per carry). Trey McBride held an average of 13.0 yds per catch by accounting for 78 yds on 6 catches. Kyler Murray finished 17-25 with 220 yds passing and 1 touchdown. He had a QB rating of 92.1 and walked away from the game with 1 interception. When it came to stopping the run, the Cardinals gave up 49 yds on 19 tries, which is an average of 2.6 yds per rush allowed. Arizona conceded 35 pass completions on 55 attempts for 303 yds, and a completion rate of 63.6%. When the final whistle blew, they ran 47 plays which gave them a total of 293 yds. The Arizona Cardinals ran the ball a total of 22 different times and compiled 82 yds, which came out to an average of 3.7 yds per attempt.

With reference to scoring touchdowns, the NFC West representatives hold an average of 23.5 points per contest. As a unit, they're holding an average of 114.0 running yds which has them ranked 13th in the NFL. The Cardinals have a total of 569 yds on the season. Arizona currently has 21 first downs as a team, and they have been called for 21 penalties for 150 yds. They have given the ball to the opposition 1 time. When talking about getting in the endzone, Arizona currently has 3 touchdowns through the air and 1 rushing touchdown.

When examining pass yds, the Cardinals have relinquished 511 yards, which is good for 26th in football. They have surrendered 255.5 total yards per outing via the pass, and are relinquishing a completion percentage of 61.4%. On the whole, they have yielded 156 yards on the ground through 2 games over the course of this season. They have allowed 3 touchdowns by way of the pass, along with 1 touchdown via the rush. On the whole, they are yielding 333.5 yds per game, which is good for 21st in professional football. They are allowing 3.8 yards per rushing attempt and 78.0 rush yards per contest for the season. The Cardinals rank 10th in the NFL when examining opponents scoring, allowing 17.5 points per outing.

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The 49ers head into this matchup 2-0 so far this season. The last time they stepped on the gridiron, the 49ers took home the win by a final score of 26-21 against the New Orleans Saints. Mac Jones (3 TDs) ended the game with 279 yards on 26-39 passing while his QB rate was 113.1. He didn't throw any picks and his Y-A was 7.2 yds. Christian McCaffrey carried the rock 13 times for 55 yds, finishing the game with 4.2 yds per attempt for San Francisco. Jauan Jennings was featured in the passing game for the 49ers, snagging 5 footballs for 89 yards (17.8 yards per catch). San Francisco ran for 3.0 yards per carry, finishing the contest with 77 yards on 26 carries. The 49ers finished with a total of 344 yds while running 65 plays (5.3 yds per play). The 49ers secondary gave up a completion percentage of 73.5%, relinquishing 186 yards on 25 for 34 passing. San Francisco relinquished 30 rush attempts for 121 yds (4.0 yds per carry).

If you analyze their ability to score points, the 49ers are ranked 18th in football, by tallying 21.5 PPG. So far this season, the 49ers have a total of 532 pass yds and average 266.0 pass yds per game, which is good for 6th in football. They have an average of 98.0 rush yards per contest, and have carried the ball for 196 yds. The San Francisco 49ers hold an average of 364.0 yds per outing, which has them sitting 8th in the league. The San Francisco offense has allowed 101 yards by way of 14 violations, ranking them 17th in the NFL if you examine helping out the opposition. They have recorded 30 first downs offensively.

The 49ers are yielding 17.0 points per contest, ranking this team at 7th in the NFL. They have surrendered 3 touchdowns via the pass and 166.0 pass yds per outing, ranking this team at 6th in the NFL. San Francisco has surrendered a total of 205 running yds (102.5 total yards per outing), and 1 touchdown to rushers this season. The 49ers defense has taken the field for 117 plays from scrimmage, which has them sitting 10th in the league. The D has recorded 3 turnovers. Overall, they have conceded 34 pts.

Who will win tonight's Cardinals-49ers NFL game against the spread?

Guy's Pick: Take the 49ers -1.5

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