The Arizona Cardinals (2-0) and San Francisco 49ers (2-0) will face off in NFL Week 3. Kickoff is set for 4:25 p.m. EDT from Levi's Stadium in Santa Clara, California. The game will broadcast live on FOX.
The 49ers are favored by -1.5 with the over/under set at 43.5 total points. The 49ers are -122 moneyline favorites to win outright; the Cardinals are +102 to pull off the upset.
In a battle for the lead in the NFC West, Mac Jones will try to hold serve against Kyler Murray and the Cards. Oddsmakers have greatly inflated the game total, giving us a great opportunity to grab value. Both defenses will rule the day in a low-scoring divisional slog.
Let's get into my 49ers vs Cardinals prediction and NFL picks for Sunday, September 21.
Cardinals vs 49ers Prediction
- Cardinals vs 49ers pick: Under 45.5; Bet to Under 44
My Cardinals vs 49ers best bet is the game total to go under. Make sure to find the best odds by checking our live NFL odds page.
Cardinals vs 49ers Odds
| Cardinals Odds | ||
|---|---|---|
| Spread | Total | Moneyline |
+1.5 -110 | 43.5 -110o / -110u | +102 |
| 49ers Odds | ||
|---|---|---|
| Spread | Total | Moneyline |
-1.5 -110 | 43.5 -110o / -110u | -122 |
Cardinals vs 49ers Week 3 Preview
Offensively, both the Cardinals and 49ers have averaged 5.2 yards per play. Both have also received the benefit of playing against the Saints defense.
Arizona was able to escape with a victory over the Panthers last week, but I wouldn’t call it an impressive offensive showing. The Cards averaged just 3.7 yards per rush, which included a 30-yard scramble from Kyler Murray.
Arizona failed to score a point after taking a 27-2 lead with 9:54 remaining in the third quarter. It also scored a defensive touchdown on the game's opening play that accounted for seven of its points.
The only difficult test for either of these offenses came in Week 1 when the Niners traveled to Seattle. The 49ers mustered 17 points on 3.3 yards per rush.
Mac Jones played well on the road last week in New Orleans, but this is going to be a step up in competition. Arizona’s defense is third in yards per pass attempt allowed and third in total defensive DVOA.
The 49ers defense has also been highly impressive. Opposing passers are averaging just 8.7 yards per completion, good for the third-best mark league-wide.
Murray is going to have to methodically move the chains, and he’ll have to do it without a consistent running game. Lead back James Conner is averaging just 3.2 yards per carry through two games.
I expect 49ers defensive coordinator Robert Saleh to be aggressive on the abundance of third and longs Murray is going to find himself in.
Another area where the Niners defense should have an edge is their ability to defend the tight end. Trey McBride is Murray’s go-to target, often commanding a 30% target share. The 49ers rank fourth in tight end coverage grade, according to Pro Football Focus.
For the 49ers offense, an ankle injury to Jauan Jennings could limit his effectiveness if he can suit up. Jennings commanded a 23% target share last week and caught seven passes the last time these two teams faced off in 2024.
Jennings’ size and experience make him a good zone-beater, something the 49ers will need against the predominant Cover-3 and Cover-4 schemes Arizona utilizes.
Since 2017, in the first four games of the season, unders inside of the division have gone 98-67, failing to reach the total at a 59.4% rate. Over the last three years in this scenario, and including two weeks of 2025, when the total is above 45 points, the under has hit at a 66.6% rate.
In Mac Jones’ entire career, divisional games have cashed at a 57.9% rate to the under. I am going to need more convincing that he can consistently perform as he did a week ago.
Cardinals vs 49ers Prediction, Betting Analysis
My personal outlook for both of these defenses heading into the season was rather optimistic — both have lived up to the billing thus far.
I will gladly take my chances playing the under by backing two top-five defenses (according to DVOA) against Murray and Jones.
Above the key number of 45, this is a tremendous value and I’d play this total down to 44.
Pick: Under 45.5; Bet to Under 44
Spread
I don't like the spread in today's game.
Moneyline
I'm also not betting on either side of the moneyline.
Over/Under
As mentioned, I see value in today's game totals.
My Pick: Under 45.5
