The San Francisco 49ers and Arizona Cardinals both suffered ugly divisional losses in Week 10, and the path forward doesn’t get any easier when they face off in Glendale in Week 11.
My early 49ers vs. Cardinals predictions and NFL picks predict a close, high-scoring matchup in the desert on Sunday, November 16.
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49ers vs Cardinals 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 49ers vs Cardinals spread pick: 49ers -3
I’m not excited about betting the spread for this game. Divisional matchups are always tough, and while the Arizona Cardinals have had a rough season, betting against a home underdog is a tough sell.
The San Francisco 49ers are 5-5 against the spread, and the Cardinals are 5-4 ATS. San Francisco has covered in four of six road matchups, while Arizona has covered in just one of four games at home.
Jacoby Brissett has done a fine job stepping up as the Cardinals’ signal-caller, but the offense is still gelling, and the defense has struggled to get stops.
San Francisco’s offense has fared equally well under backup Mac Jones, but Brock Purdy could return on Sunday.
The Niners defense has played poorly, but not quite as poorly as the Cardinals. This one feels closer to a Pick'em, but I’ll lean on the team with the more talented roster that is 4-2 ATS on the road.
Early 49ers vs Cardinals total pick: Over 48.5
San Francisco is 6-3-1 to the Over this season, while Arizona is 5-4. Over the last four games, Arizona’s offense has averaged 24.8 points, and San Francisco’s has posted 21.3.
In that same span, the 49ers have allowed 25.5 points per game, and the Cardinals have surrendered 28.8. The Niners are 4-1-1 to the Over on the road, and the Cardinals are 3-1 to the Over at home.
With both defenses giving up points in bunches, I’ll bet the Over on this divisional clash.
49ers vs Cardinals odds
- 49ers vs. Cardinals spread: Cardinals +3
- 49ers vs. Cardinals moneyline: 49ers -156, Cardinals +132
- 49ers vs. Cardinals Over/Under: 48.5
How to watch 49ers vs Cardinals
- 49ers vs. Cardinals matchup
- Date: Sunday, November 16, 2025, 4:05 p.m. ET
- City: Glendale, AZ
- Venue: State Farm 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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