With nothing on the line in this NFC West matchup, except for the loser having a higher draft pick, the San Francisco 49ers could be in for an ugly close to the regular season against the Arizona Cardinals.
Down Brock Purdy, and with Joshua Dobbs starting for San Francisco, I’m expecting Arizona to be positioned to end its season on a high note in my 49ers vs. Cardinals predictions.
Read on for my NFL picks for Sunday, January 5 with kick-off set for 4:25 p.m. ET, live on FOX.
49ers vs Cardinals prediction
- Moneyline prediction: Cardinals moneyline (-230)
- Spread prediction: Cardinals -5 (-110)
- Over/Under prediction: Under 42.5 (-110)
- Best bet: Kyler Murray Over 31.5 rushing yards (-125)
49ers vs Cardinals spread predictions
If San Francisco was at full strength, it would likely be favored by a point or two. But with Dobbs in there, Arizona has a clear advantage, on top of being at home. While Kyler Murray’s season has been erratic, he’s still 14th in EPA per play among QBs and should get after a 49ers defense that’s been a disappointment for much of the year.
Even without James Conner, the Cardinals can make a big enough dent in a San Francisco defense that’s just 21st in EPA per play. The Cardinals are 10-6 ATS this year.
49ers vs Cardinals moneyline predictions
It’s hard to imagine a world where Dobbs wins a game in his first start of the season, but we’ve seen the Passtronaut pull off crazier feats. However, he’s just 3-11 in his career as a starter, which includes going 1-7 for Arizona last season. While Jonathan Gannon’s defense has left a lot to be desired this year, this is the easiest QB matchup it’s had all season. Plus, the 49ers are down Deebo Samuel Sr. with George Kittle listed as questionable.
49ers vs Cardinals Over/Under prediction
San Francisco’s offense looks almost nothing like the one that nearly won the Super Bowl last year. It’s without Purdy, Samuel, and potentially Kittle, on top of already being down Christian McCaffrey, Trent Williams, Brandon Aiyuk, and Jordan Mason. Even right tackle Colton McKivitz is questionable.
If the 49ers score more than 17 points, I’ll be shocked. While the Cardinals are in a better position, this offense is still just 15th in points per game (22.1) and without its best player (Conner). I have Arizona winning 23-17.
My best bet
Kyler Murray Over 31.5 rushing yards (-125 at BetMGM)
My analysis
This San Francisco 49ers defense has been far from what you’d expect given all of the All-Pro talent on it. And although it’s in a better spot than the offense, it’s dealing with a slew of injuries too.
Nick Bosa and Leonard Floyd are banged up, Deommodore Lenoir is out, and both Dre Greenlaw and Javon Hargrave are on IR. That should allow an already run-oriented Arizona Cardinals offense to have a strong outing.
Arizona is ninth in EPA per rush, and while Conner isn’t suiting up, offensive coordinator Drew Petzing would be smart to still lean on his rushing attack - the 49ers are 28th in EPA per rush on defense.
With veteran journeyman Michael Carter starting at running back, that should mean Kyler Murray being featured more in the ground game. He’s fourth in the league in rushing yards among QBs this season (550) and second in yards per carry (7.3).
Murray is averaging 34.4 rushing yards per game and has already topped 31.5 in eight games this season, including in each of his last two. His ability to create as a runner should be a problem for the 49ers, with Murray averaging 3.12 yards per carry after contact and sitting fifth in 10-plus-yard runs among QBs (19).
This is the perfect matchup for Murray to lean on his mobility.
49ers vs Cardinals same-game parlay
Kyler Murray Over 31.5 rushing yards
Marvin Harrison Jr. Over 55.5 receiving yards
Isaac Guerendo anytime TD scorer
It won’t just be Murray turning in a strong performance, his top five pick at receiver should close out the year with a bang. Although Marvin Harrison Jr. hasn’t had quite the season many hoped, he’s still had some impressive moments.
He’s fifth in receiving yards among rookies (822) and second in contested catches (16). That will come in handy against a 49ers defense dealing with injuries in the secondary. Harrison is coming off one of his best games of the season (96 yards) and can build on it against San Fran.
He’s not the only rookie who could pop though. With Isaac Guerendo looking healthy, he should find the end zone. The fourth-round pick out of Louisville has scored three times in his last four games and takes on a Cardinals defense that’s 25th in EPA per rush.
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More NFL picks and odds from Covers
49ers vs Cardinals odds
49ers vs Cardinals live odds
49ers vs Cardinals opening odds
- Spread: San Francisco -1 | Arizona +1
- Moneyline: San Francisco +180 | Arizona -225
- Over/Under: Over 46.5 | Under 46.5
Odds courtesy of BetMGM
49ers vs Cardinals spread and Over/Under analysis
- The 49ers opened as a 1-point favorite, but this line has moved several points in the opposite direction with the Cardinals being offered at -4.5 due to Purdy being out.
- Arizona is among the best teams ATS this season at 10-6, with San Francisco just 5-11.
- After the Over/Under opened as high as 46.5, it’s steadily dropped down and is now at 42 due to Purdy’s injury.
- The 49ers are a solid 9-7 betting the Over, but the Cardinals are just 7-8-1.
49ers vs Cardinals betting trend to know
The San Francisco 49ers have only hit the team total Over in seven of their last 21 games (-10.50 Units / -39% ROI). Find more NFL betting trends for 49ers vs. Cardinals. Find more NFL betting trends for 49ers vs. Cardinals.
49ers vs Cardinals game info
| Location: | State Farm Stadium, Glendale, AZ |
| Date: | Sunday, 1-5, 2025 |
| Kickoff: | 4:25 p.m. ET |
| TV: | FOX |
49ers vs Cardinals latest injuries
49ers vs Cardinals weather
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