The San Francisco 49ers are getting healthy at long last, but their luck may be running out ahead of today’s NFC West showdown with the Arizona Cardinals.
My 49ers vs. Cardinals predictions detail why Arizona should be respected more in this spot, and how San Francisco’s issues extend beyond the injury report.
Here are my free NFL picks ahead of kickoff from State Farm Stadium at 4:05 p.m. ET on FOX.
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49ers vs Cardinals prediction
49ers vs Cardinals Best bet: Cardinals +3 (-105)
After a blazing hot start to the season, the San Francisco 49ers are now 6-4 and 5-5 against the spread, which is to say the 49ers are right where they belong to be.
For much of the year, San Francisco has had the benefit of an easy schedule and some luck turning its way in close games. It ranks just 24th in defensive DVOA, and on offense, its metrics are buoyed by the eighth-best grade in passing DVOA, while the ground game has continued to struggle.
Now, much of the reason I’ve been sour on the 49ers — at least offensively — is their nagging injuries. At least in this game, they’ll have their cleanest bill of health in a while with Ricky Pearsall returning and Jauan Jennings mercifully off the injury report.
The problem is that now Brock Purdy is healthy, too, so this team will once again rotate at the quarterback position. Purdy is just 1-1 on the year with four touchdowns and four interceptions, and while he’s completed 65.8% of his passes for 586 yards, the jury is still very much out – especially after his somewhat rocky 2024 season.
With that all said, the Cardinals’ secondary has been surprisingly good this year. They rank ninth in DVOA against the pass and eighth in yards per attempt, and I think oddsmakers were too quick to lose faith in the Arizona Cardinals after it went up against the best passing offense in football.
Arizona’s offense may not be fantastic, but we saw last week in a loss to the Los Angeles Rams just how badly this 49ers defense can be exposed. Jacoby Brissett has been solid for the Cardinals, too, even against great defenses – and he’s made it work without some of his top weapons available on offense.
There’s just too much unknown with this 49ers offense going back to Purdy, and I don’t think it’ll have a ton of success against what’s been an excellent secondary. We know San Francisco can’t run, either, and the last time these teams met, the 49ers scored just one touchdown.
We just need Arizona to score, and it should.
49ers vs Cardinals same-game parlay
Trey McBride is an easy write-in for our parlay here. There are several names either missing or potentially missing on offense for Arizona, with Marvin Harrison, Jr. out and Bam Knight questionable, so in close, I expect Brissett to keep looking for his tight end.
McBride has been targeted 19 times in the red zone — the second-most of any player — and the 49ers are not only allowing the sixth-most targets to his position but the third-most in the red zone.
Sticking at the tight end position, we’ll also grab this line on George Kittle’s receptions after he caught all nine targets last week against L.A.. The Cardinals are ranked just 14th in DVOA against the tight end position with several names out at linebacker, and they’ve allowed the 10th-most targets to opposing tight ends.
49ers vs Cardinals 3-leg SGP
- Cardinals +3
- Trey McBride anytime touchdown
- George Kittle Over 4.5 receptions
Our big-ticket SGP: Rollin' the dice!
If you really want to roll the dice here, I recommend looking to the slot receivers. With Harrison out, Greg Dortch should be thrust into action in the slot, where the 49ers rank second-worst in DVOA.
Much of San Francisco’s secondary has struggled, but slot corner Upton Stout has been the second-worst of 112 at his position in coverage according to Pro Football Focus.
The Cardinals have also struggled to defend slot receivers, ranking just 25th in DVOA, and Jauan Jennings is now fully healthy and thriving at that position.
He hauled in six of nine targets for 71 yards last week and should get enough volume here to hit his yardage number with the 49ers averaging the fourth-most attempts per game.
49ers vs Cardinals 5-leg SGP
- Cardinals +3
- Trey McBride anytime touchdown
- George Kittle Over 4.5 receptions
- Greg Dortch Over 3.5 receptions
- Jauan Jennings Over 48.5 receiving yards
49ers vs Cardinals game predictions
49ers vs Cardinals moneyline prediction
Arizona would be my pick on the moneyline here, standing tall as the team with the far better defense and an offense that has still been capable of scoring a few times on strong defenses under Jacoby Brissett.
49ers vs Cardinals spread prediction
This line was sitting at 1.5 points when Kyler Murray was still healthy, and after moving to three, it’s remained more or less stagnant.
49ers vs Cardinals Over/Under prediction
The Under here could be in play after both teams played to a 16-15 finish earlier in the year. San Francisco’s offense should encounter enough turbulence here, so if you aren’t sold on the Cardinals running up the score, it’s a good place to go.
49ers vs Cardinals odds
- Spread: 49ers -3.5 (-106) | Cardinals +3.5 (-114)
- Moneyline: 49ers -190 | Cardinals +160
- Over/Under: Over 48.5 (-106) | Under 48.5 (-114)
More NFL picks and odds from Covers
49ers vs Cardinals trend to know
The Cardinals have hit the 3Q moneyline in 10 of their last 16 games (+8.70 Units / 40% ROI). Find more NFL betting trends for 49ers vs. Cardinals.
How to watch 49ers vs Cardinals
| Location | State Farm Stadium, Glendale, AZ |
| Date | Sunday, November 16, 2025 |
| Kickoff | 4:05 p.m. ET |
| TV | FOX |
49ers vs Cardinals latest injuries
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