San Francisco 49ers vs. Arizona Cardinals Picks and Prediction, Sunday November 16, 2025
The NFL season is past the halfway point as races heat up across the league, and on Sunday, we'll see a key NFC West showdown with our San Francisco 49ers vs. Arizona Cardinals prediction.
The San Francisco 49ers (6-4) were overlooked coming into this season, but with one of the most balanced teams in the NFL, they've been very good in 2025, and with the top spot in the NFC West still available to them, this is a key matchup.
On Sunday, they take on the Arizona Cardinals (3-6), a team that has some intriguing talents, but without the depth and balance of other teams in the NFC West, they're well and truly out of the playoff race and on the way to another very disappointing campaign. Read on to see our San Francisco 49ers vs. Arizona Cardinals prediction.
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Can the 49ers stay alive in the NFC West division race?
The San Francisco 49ers have been one of the NFL's most consistent teams in the past decade, and with the team posting a very impressive 4-2 record away from home this season, they could be a major threat in the NFC once more in 2025. At 5-4, the Niners are still in the playoff race, but Seattle and the LA Rams are both 7-2 at the top of the division. Unlike recent seasons, this 49ers offense hasn't been fantastic, as they average just 22 points a game, but with the defense once again being very solid, holding opponents to just 23 points a game, they've managed to keep themselves in every game this year.
This week, the 49ers will turn to Brock Purdy once more after a six-week injury absence, with the talented starter posting a 4/4 TD/INT ratio in his first two games, and with just six total rushing TDs this season, it's safe to say that much more emphasis has been placed on their passing game. Last time out, San Francisco lost do division-rival Los Angeles Rams, with the team passing for over 300 yards in this one, but with two crucial turnovers at tough times in this game, the 49ers fell to their NFC rival 42-26.
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Key Injuries for the 49ers
- WR Ricky Pearsall (knee) is questionable.
- CB Deommodore Lenoir (calf) is questionable. Has 24 tackles and one pick
- LB Dee Winters (knee) is questionable. Has 47 tackles.
Can the Cardinals pick up a major NFC West upset?
The Arizona Cardinals started 2025 with wins in two straight games, but since that point, they've struggled mightily, going 1-6 in their next seven, as they've once again fallen to last place in the NFC West, with their record sitting at 1-3 in games played at home this season. While the Cardinals' defense is solid, holding opponents to just 24 points a game this season, but given that they score just 22 a game themselves, they've just not managed to have any luck this season as they continue their struggles in a big way.
| # | Handicapper | Profit |
|---|---|---|
| 1 |  Marc David | +521.00 |
| 2 |  Rob Vincilleti | +502.00 |
| 3 |  Bruce Marshall | +471.00 |
| 4 |  Patty Reyes | +400.00 |
| 5 |  Mike Lundin | +288.00 |
With Kyler Murray out for the season, Arizona once again turns to veteran Jacoby Brissett this week, with the 32-year-old tossing an impressive eight touchdowns in his role this season, and with just one turnover, he's the clear starter for this team moving forward. He will be missing a key weapon with WR Marvin Harrison Jr. out for this week due to surgery. Last time out for the Cardinals was a big loss at the hands of the Seattle Seahawks, with Brissett having a very tidy game in this one, but with Seattle putting up 372 total yards, they finished much better as the Cardinals came up short in a 44-22 blowout.
Key Injuries for Cardinals:
- C Evan Brown (foot) was limited in practice on Thursday. Is questionable.
- OG Wil Hernandez (knee) is questionable.
- LB BJ Ojulari (knee) was limited on Thursday. Is questionable. Has 23 tackles and four sacks.
- S Dadrion Taylor-Demerson (ankle) is questionable. Has two picks and 21 tackles.
- QB Kyler Murray (foot) is on the IR.
- WR Marvin Harrison Jr. (appendicitis) is out. Has 34 catches for 525 yards and four TDs.
San Francisco 49ers vs. Arizona Cardinals picks
Moneyline pick for 49ers vs. Cardinals
- San Francisco -3 (4 units)
On paper, this is a matchup that favors the San Francisco 49ers in a big way, and in their last 10 head-to-head matchups, it's the road team in this one that has a dominant 6-4 record. Purdy should give the offense the lift it needs, even though Mac Jones did a solid job in his place.
Earlier this season, the 49ers picked up a tight 16-15 win over Arizona at home, but with the team finding its consistency in recent times, expect them to pick up another win here on the back of their 4-2 road record this season as they remain in the NFC West race.
Over/under pick for 49ers vs. Cardinals
- Over 44 (4 units)
Neither of these teams has been explosive on either side of the ball thus far, but in their last three head-to-head encounters in Arizona, the average total points between these NFC West rivals has been 64. Purdy can run more than Mac Joes so they can be a little more dynamic with him at quarterback.
For the 49ers, the over sits at 6-3-1 in their last 10 overall games, with 25 or more points allowed in six of those games, and for the Cardinals, the over comes in at 6-4 in their past 10, with 23 or more points allowed in six of their games played this season.
Keep it simple, take the over.
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