The 49ers host the Cardinals as 8.5-point favorites on Sunday, Sept. 27 in an NFC West showdown.
My Cardinals vs. 49ers predictions believe injuries to San Francisco's defense and receiving corps could help dictate the pace, while both quarterbacks have favored shorter throws.
My NFL picks for Week 3 break down how that could shape the total.
Cardinals vs 49ers prediction: Under 47.5
Despite San Francisco 49ers All-Pro edge rusher Nick Bosa being ruled out, I still like the Under down to 46.5 in Week 4 against the Arizona Cardinals.
Bosa's absence will force defensive coordinator Raheem Morris to play his secondary deeper in coverage to prevent big plays because he is less confident in San Francisco's pass rush. The Niners are also missing two wide receivers from their opening day roster, and WR Mike Evans hasn't practiced this week.
Arizona QB Jacoby Brissett is 28th in intended air yards per pass and has the best interception rate in NFL history, while 49ers QB Brock Purdy is 29th in intended air yards per pass and hasn't thrown a pick this season.
I'm counting on plenty of checkdowns to keep the clock running and few turnovers to create defensive touchdowns or short fields for the opposing offense.
COVERS INTEL: The 49ers are tied for the second-most seconds per play in the NFL, and pace is the most important thing for handicapping totals. 
Cardinals vs 49ers combo
I'm mixing Arizona's +4.5 first-half spread into my combo even though I lean toward the Niners covering their full-game spread.
The Cardinals led at halftime of their 26-14 Week 1 win over the Los Angeles Chargers, and were tied at halftime in their 31-7 loss to the Seattle Seahawks last week.
San Francisco averages 7.0 more points per game in the second half (19.0-12.0) and wears teams down with its ground game, as the 49ers are sixth in rushing rate. My game script is a slow-paced battle without back-breaking turnovers, with the Niners pulling away late.
Finally, McCaffrey is one of the best receiving running backs in league history. He's fresh off his third season of 100+ receptions, and already has nine grabs this season.
Cardinals vs 49ers combo
- Under 47.5
- Arizona +4.5 1H
- McCaffery 5+ receptions
Cardinals vs 49ers touchdown scorer: Deebo Samuel
I'm sure Niners WR Deebo Samuel is happy to be back in the Bay Area after wasting away with the Washington Commanders last season.
Deebo's target share should increase with the injuries to San Francisco's wideouts. I'm guessing Evans plays this week, and Arizona uses its best outside corner to cover him.
According to Pro Football Focus, Cardinals nickelback Denzel Burke is lining up across from Samuel, who mostly lines up in the slot. Burke is 86th in pass coverage grade out of 91 qualified cornerbacks. Plus, Deebo gets carries and has 22 career rushing touchdowns.
- Top picks: 2-6, -4.19 units
- Combos: 2-6, +1.50 units
Cardinals vs 49ers odds
For help understanding probabilities, see our odds calculator.
- Spread: Cardinals +8.5 | 49ers -8.5
- Over/Under: Over 47.5 (55%) | Under 47.5 (50%)
- Moneyline: Cardinals 23% | 49ers 80%
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Cardinals vs 49ers weather
It will be about 66°F in Santa Clara on Sunday with 9-mph winds and no chance of rain.
Check out our NFL weather page for up-to-date info on every matchup.
Cardinals vs 49ers trend to know
Arizona has gone Under the total in both games this season by an average of 5.0 points per game. Find more NFL betting trends for Cardinals vs. 49ers.
How to watch Cardinals vs 49ers
| Location | Levi's Stadium, San Francisco, Calif. |
| Date | Sunday, Sept. 27, 2026 |
| Kickoff | 4:05 p.m. ET |
| TV | FOX |
Cardinals vs 49ers latest injuries
Check out our NFL injuries page for updates on every team.
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