The Arizona Cardinals are off to a stellar 2-0 start this season, but after an easy walk through two good opponents, they’ll now have to combat the unbeaten San Francisco 49ers.
My Cardinals vs 49ers predictions will focus on Arizona’s performance on both sides of the ball in the run game and explain why we may have to pump the brakes on San Francisco after just one win behind its backup quarterback.
Read below for my free NFL picks for Sunday, September 21.
Cardinals vs 49ers prediction
Cardinals vs 49ers Best bet: Cardinals +2.5 (-115)
I’m starting to believe in the Arizona Cardinals, and on the opposite side of the coin, I’m very hesitant to buy into the San Francisco 49ers after one big win over a terrible New Orleans Saints secondary.
The fact remains, the way to beat the Cardinals is through the air. Their secondary came into the season with plenty of questions that needed answering, and that’s a big reason why opponents have thrown the most passing attempts against them through two weeks.
Well, it hasn’t exactly been smooth sailing for the Cardinals’ opponents. Yes, they’ve had a weak schedule, but we’ve seen better secondaries struggle against bad offenses. They’ve allowed just 5.4 yards per attempt, ranked third in the league, and their run defense has graded out above-average according to Pro Football Focus.
Now, we’ve got a banged-up 49ers team, which is down George Kittle and starting quarterback Brock Purdy, and a Cardinals team that has run the ball to great success and ranks 12th with 4.7 yards per carry.
Arizona can beat you in a myriad of ways offensively, but the big deal here is the defense. I’m not very confident that Jones can replicate his success from Week 2, and on the opposite end, the 49ers defense has been just a notch below where they’ve been for years, with the rushing defense looking very suspect — checking in fifth-worst according to PFF.
In a battle on the ground, you’ve got to like the Cardinals, given the defensive line’s excellent play and the offensive line’s ability to slow solid pass rushes.
Cardinals vs 49ers same-game parlay
There’s a story developing here in the Cardinals' backfield, and that’s the emergence of Trey Benson. The second-year back saw 44% of the snaps last week after taking the field for 33% in the opener, and it’s no surprise given he’s now averaged 7.5 yards on 11 carries. I recognize this is a back who’s liable to get more active in the passing game, but San Francisco hasn’t been very generous through the air to this position.
I’m also going to back Mac Jones here despite the strong nature of Arizona’s secondary, because while he may ultimately fail, there’s no denying he’ll be airing it out all game long.
Cardinals vs 49ers SGP
- Cardinals +2.5
- Trey Benson Over 26.5 rushing yards
- Mac Jones Over 219.5 passing yards
Our big-ticket SGP: Plenty of offense in Santa Clara
- I didn’t want to add in Kyler Murray’s rushing yards above in the interest of lengthening out the odds, but it’s worth noting the 49ers allowed over five yards per carry to the position last year, and Murray has now carried seven times through two games, hitting this number in both contests.
- The Cardinals are also the worst team in the league versus the tight end position this year, and while we can’t bet on Jake Tonges’ yardage prop, we’ll settle on a touchdown — something he’s already recorded this season.
Cardinals vs 49ers SGP
- Cardinals +2.5
- Trey Benson Over 26.5 rushing yards
- Mac Jones 225+ passing yards
- Jake Tonges anytime TD
- Kyler Murray Over 28.5 rushing yards
Cardinals vs 49ers odds
- Spread: Cardinals +1.5 | 49ers -1.5
- Moneyline: Cardinals +105 | 49ers -120
- Over/Under: Over 42.5 | Under 42.5
More NFL picks and odds from Covers
Cardinals vs 49ers trend to know
The San Francisco 49ers have covered the 1Q Spread in 15 of their last 19 games (+11.85 Units / 55% ROI). Find more NFL betting trends for Cardinals vs. 49ers.
How to watch Cardinals vs 49ers
| Location | Levi's Stadium, Santa Clara, CA |
| Date | Sunday, September 21, 2025 |
| Kickoff | 4:25 p.m. ET |
| TV | FOX |
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