We have the Arizona Cardinals and San Francisco 49ers facing off at Levi’s Stadium in Week 3. Both teams have started the season hot and top the NFC West with two wins apiece.
My Cardinals vs 49ers predictions and NFL picks have the 49ers covering the spread despite uncertainty at quarterback. Tune in for the 4:25 p.m. ET kickoff on Sunday, September 21.
Cardinals vs 49ers predictions
Here are our early thoughts on the spread and total for this week’s game. We will have a full game preview (with a best bet and SGP) later in the week.
Early Cardinals vs 49ers spread pick: 49ers -1.5
Early in the week, we’re always facing uncertainty around potential lineups and dealing with the aftermath from Sunday’s matchups. The Arizona Cardinals' trip to the Bay Area is no different, mostly due to the status of San Francisco 49ers quarterback Brock Purdy.
Purdy missed Week 2 and, per Adam Schefter, the team is “not optimistic” that he will return in time for this game.
A fit Purdy instantly upgrades this 49ers offense despite Mac Jones leading the team to a win last time out. That said, the team only beat a poor 0-2 Saints team by five points.
Since opening, this line has already moved significantly, with the 49ers going from 3.5 to 1.5-point favorites, and further news, positive or negative, around Purdy could move the spread further.
Before rushing to back Arizona, it’s worth noting that the Cardinals haven’t lit up either of their games, and in facing the Panthers and Saints, they’ve faced two of the weakest teams in the NFC.
Jones is far from an elite quarterback, but Kyle Shanahan believed in him during the draft process - even though they ultimately went with Trey Lance - and he did throw three touchdown passes in his debut.
The 49ers offense is no longer a juggernaut, but Jones led them to 26 points against the Saints last Sunday, one more than Kyler Murray managed the week before.
The homefield advantage will prove to be enough for San Francisco to eke past the visiting Cardinals.
Early Cardinals vs 49ers total pick: Over 43.5
Through two games, the total is 1-1 for both teams.
The Cardinals have scored at least 20 points in both of their games, and Murray will be licking his lips at facing the 49ers defense.
It’s been a long time since this was an elite defensive unit, as we saw when Alvin Kamara rushed for 99 yards and Spencer Rattler tossed three touchdown passes against them in Week 2.
The 49ers have only given up 34 points in two games, but they haven't looked very strong overall, even when they managed to stop Sam Darnold from throwing a single touchdown pass.
The offense was far from explosive against the Saints, but Jones did a reasonable job of game management. He completed 26 of 39 pass attempts and kept the offense humming.
We have two capable offenses facing flawed defenses, and we should expect to cover the total. Last season, the two games between these teams had 47 and 71 points, respectively.
Cardinals vs 49ers odds
- Cardinals vs. 49ers spread: 49ers -1.5
- Cardinals vs. 49ers moneyline: Cardinals +102, 49ers -120
- Cardinals vs. 49ers Over/Under: 43.5
How to watch Cardinals vs 49ers
- Cardinals vs. 49ers matchup
- Date: Sunday, September 21, 2025, 4:25 p.m. ET
- City: Santa Clara, CA
- Venue: Levi's Stadium
- TV: FOX
Odds are correct at the time of publishing and are subject to change.
Not intended for use in MA.
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