Cardinals vs. 49ers Final Score Prediction for NFL Week 3 (Arizona to Upset?)

Can the Cardinals pull off an upset in Week 3?

The Arizona Cardinals and quarterback Kyler Murray are 2-0 this season. / Matt Kartozian-Imagn Images

The Arizona Cardinals and San Francisco 49ers are both 2-0 in the 2025 season heading into Sunday’s matchup in San Francisco.

Arizona has played a couple of weak opponents – Carolina and New Orleans – to open the campaign, but it has been able to win both games, covering in one. The 49ers have gone 2-0 against the spread in 2025, winning with Mac Jones under center for the injured Brock Purdy in Week 2. 

San Fran has been extremely banged up on offense, but oddsmakers still have it favored in this divisional battle. 

Each week at SI Betting, we’re attempting to predict the final score of each NFL game as a fun exercise to guide bettors in the total and spread bets for the week’s slate.

Using the latest odds and analysis from our NFL betting team, here’s where I’m leaning for the Cardinals-49ers matchup in Week 3. 

Cardinals vs. 49ers Odds, Spread and Total

Odds via DraftKings Sportsbook

Spread

• Cardinals +2.5 (-105)
• 49ers -2.5 (-115)

Moneyline

• Cardinals: +130
• 49ers: -155

Total

• 45.5 (Over -105/Under -115)

This line has actually moved a point in favor of the 49ers, although it could end up closing closer to Arizona depending upon the final status for Brock Purdy in Week 3. 

Cardinals vs. 49ers Final Score Prediction

The 49ers are No. 1 in the NFL in defensive EPA/Play this season, but they’ve also faced two subpar offenses in the Seattle Seahawks and the New Orleans Saints.

A lot of this game comes down to who is under center for the 49ers, but a less than 100 percent Brock Purdy is still not a perfect option.

Arizona has taken a lot of heat for not dominating the Saints and Carolina Panthers in the first two weeks of the campaign, but it won both games and covered in the other. The Cards also have the No. 12 EPA/Play on offense during that stretch. 

San Francisco is depleted on offense due to injuries, and I think the Cards have stooped to the level of their opponents – especially in the second half of Week 2 against Carolina – so far this season.

I’m buying Kyler Murray and company to pull off a division upset – especially if Mac Jones is under center for San Fran.  

Final Score Prediction: Cardinals 23, 49ers 20

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Odds refresh periodically and are subject to change.

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