Arizona Cardinals vs San Francisco 49ers Prediction, 9/27/2026 NFL Picks, Best Bets & Odds Week 3

Game: Arizona Cardinals vs San Francisco 49ers

Date: Sunday, September 27, 2026

Location: Levi's Stadium in Santa Clara, CA

TV: FOX

Odds-Point Spread: Cardinals +8.5

Total-Over-Under: 47

The Arizona Cardinals (1-1) are hitting the road to Levi's Stadium on Sunday where they will try to defeat the San Francisco 49ers (2-0). San Francisco opens this matchup as 8.5-point favorites from Vegas oddsmakers. The total is 47.

The Arizona Cardinals head into this matchup 1-1 this year. When they last stepped on the football field, the Cardinals faced off with the Seattle Seahawks and walked away from this one with a loss by a score of 31-7. Jacoby Brissett went 17-28 with 95 yds passing and 1 TD. He had a QB rate of 63.8 and ended the contest with 1 interception. Jeremiyah Love was the best rusher for the Cardinals with 9 carries for 29 yds (3.2 yds per attempt). Trey McBride held an average of 5.1 yards per catch by totaling 41 yds on 8 receptions. The Arizona Cardinals ran the football 17 different times and accrued 70 yards, which earned them an average of 4.1 yards per tote. On the day, they ran 45 plays which totaled 151 yards. Arizona surrendered 19 pass completions on 26 attempts for 219 yards, and a completion percentage of 73.1%. Against the run, the Cardinals conceded 162 yards on 40 tries, which averages out to 4.1 yards per rush allowed.

Regarding scoring points, the Arizona Cardinals hold an average of 16.5 points per game. Offensively, they are averaging 93.0 running yds which is 24th in the league. The Cardinals have compiled 544 yds for the year. Arizona has accrued 19 first downs as a unit, and they have been called for 14 infractions for 159 yds. They have turned the football over 1 time. When it comes to notching touchdowns, Arizona has recorded 2 touchdowns through the air and 1 rushing touchdown.

Regarding pass yds, the Cardinals have conceded 406 yards, which ranks 14th in the NFL. They have granted 203.0 yards per game by way of the pass, and are granting a completion rate of 67.9%. All in all, they have allowed 243 rushing yards through 2 outings for the season. They have granted 4 touchdowns through the air, along with 2 touchdowns on the ground. In total, they are yielding 324.5 yards per game, which is good for 14th in the league. They are giving up 4.0 yards per rush and 121.5 running yds per contest over the course of this year. The Cardinals currently rank 14th in football when it comes to team defense, yielding 22.5 points per contest.

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The 49ers step onto the field with a record of 2-0 over the course of this season. In their last contest, the 49ers took home the win by a final score of 35-13 against the Miami Dolphins. Brock Purdy ran the football 3 times for 30 yds, ending the game with 10.0 yards per attempt for San Francisco. George Kittle was one of the featured targets for the 49ers, hauling in 4 footballs for 80 yards (20.0 yds per catch). Brock Purdy (2 touchdowns) walked away from the contest with 287 yds on 20-22 passing while his quarterback rating was 149.1. He didn't toss any interceptions and his avg yards per attempt was 13.0 yds. San Francisco allowed 29 running attempts for 102 yards (3.5 yards per rush). The 49ers pass defense gave up a completion percentage of 60.9%, surrendering 182 yards on 14 for 23 passing. The 49ers finished with 382 yds while running 49 plays (7.8 yds per play). San Francisco ended up running for 3.5 yds per attempt, finishing the game with 95 yards on 27 attempts.

The San Francisco 49ers maintain an average of 380.5 total yards per contest, giving them a rank of 8th in the NFL. They average 134.5 running yds per contest, and have carried the ball for 269 total yards. They have a total of 1 interception while relinquishing no fumbles lost, and have recorded 28 first downs. The San Francisco offense has granted 99 yds on 9 violations, which has them sitting 28th in football when it comes to hurting your team. On the season, the 49ers have earned 492 passing yds and have an average of 246.0 passing yds per contest, giving them a rank of 8th in the NFL. Regarding this team's ability to score points, the 49ers currently rank 5th in football, maintaining an average of 31.0 points per contest.

They have given up 1 touchdown through the air along with 175.0 yards via the pass per game, ranking this team at 9th in the NFL. San Francisco has allowed a total of 224 rush yds (112.0 total yards per game), along with 1 touchdown to runners over the course of this season. Their defense has accrued 2 turnovers (1 fumble and 1 interception) for the year. All in all, they have yielded 20 points in total. The 49ers defense has taken part in 113 plays, giving them a rank of 9th in football. The 49ers are conceding 10.0 points per outing, ranking this team at 3rd in the NFL.

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

Guy's Pick: Take the Cardinals +8.5

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