San Francisco 49ers vs Arizona Cardinals: In the NFC West, Kyler Murray and the Cardinals travel to Northern California to face either Mac Jones or Brock Purdy and the 49ers.
Just a week ago, 49ers coach Kyle Shanahan called Purdy a “long shot” to play against the Saints. The tone shifted a few days ago: “He does have a chance [to play].” However, we now know it&#8217;s going to be Jones.
Purdy has been dealing with a toe and shoulder injury that he suffered in Week 1 against the Seahawks. He was a limited participant in practice this week. 
Does Mac Jones still give the 49ers a quality opportunity to win and cover the spread? Let’s break it down with my San Francisco 49ers vs. Arizona Cardinals picks and predictions.
For additional information on picks, props, moneylines, and more on today’s slate, take a look at our <a href="/nfl/picks/" target="_blank" rel="noopener">NFL Picks Page</a> or our <a href="/nfl/odds/" target="_blank" rel="noopener">NFL Odds Page</a>.
You can also browse our recommendations for the <a href="/best-online-sportsbooks/" target="_blank" rel="noopener">best online sportsbooks</a> available in the U.S.
<h2><a href="/nfl/matchup/2025-09-21-arizona_cardinals-san_francisco_49ers-n-1/" target="_blank" rel="noopener">San Francisco 49ers vs Arizona Cardinals NFL Betting Insights</a></h2>
&nbsp;
<div id="attachment_29142" style="width: 511px" class="wp-caption aligncenter"><img loading="lazy" decoding="async" aria-describedby="caption-attachment-29142" class=" wp-image-29142" src="https://wp.bettingnews.com/wp-content/uploads/2022/12/1200x0_43384f112852558ebcd3a2afc6734708_2000-e1706028825955-300x169.jpg" alt="Brock Purdy leads the 49ers this NFL season" width="501" height="282" srcset="https://wp.bettingnews.com/wp-content/uploads/2022/12/1200x0_43384f112852558ebcd3a2afc6734708_2000-e1706028825955-300x169.jpg 300w, https://wp.bettingnews.com/wp-content/uploads/2022/12/1200x0_43384f112852558ebcd3a2afc6734708_2000-e1706028825955-1024x575.jpg 1024w, https://wp.bettingnews.com/wp-content/uploads/2022/12/1200x0_43384f112852558ebcd3a2afc6734708_2000-e1706028825955-768x431.jpg 768w, https://wp.bettingnews.com/wp-content/uploads/2022/12/1200x0_43384f112852558ebcd3a2afc6734708_2000-e1706028825955.jpg 1200w" sizes="auto, (max-width: 501px) 100vw, 501px" />Will Brock Purdy be ready to play this Sunday?</div>
QB Battle: Realistically, no &#8211; there isn’t a true quarterback duel between Purdy and Jones right now. But somewhere down the line, that could change.
Remember, Shanahan originally wanted to draft Mac Jones instead of Trey Lance &#8211; a decision the 49ers clearly regret. Shanahan has a track record of maximizing average quarterbacks, with Purdy being the prime example.
That said, Purdy hasn’t looked as sharp as in years past, showing some regression. Meanwhile, Jones looked terrific last week against the Saints, going 26-for-39 with 279 yards, three touchdowns, and no interceptions. Yes, it was the Saints &#8211; but that’s still a respectable defense.
It&#8217;s not surprising that the 49ers didn&#8217;t try to rush Purdy back; if he isn&#8217;t 100%, there&#8217;s no need to force him to play. San Francisco made the right call with Jones, who showed enough to prove he can manage this offense, and Shanahan likely sees it the same way.
Cardiac Cardinals: Arizona nearly gave their fans &#8211; and plenty of survivor contestants &#8211; a scare on Sunday when they almost squandered a 27-3 lead against the lowly Carolina Panthers.
Fortunately, for all involved (myself included with a survivor entry riding on them), they held on and now sit at 2-0.
In the desert, the conversation has centered on the limited usage of second-year receiver Marvin Harrison Jr. He saw five targets but managed only two catches for 27 yards. The week prior, he was far more impactful, hauling in five of six targets for 71 yards and a touchdown.
Overall, this Cardinals team looks like a solid, playoff-caliber group. Defensively, they’ve surrendered just 35 total points while holding opponents to 4.6 yards per play &#8211; numbers that would look even better had they not melted down in garbage time against Carolina.
On offense, Arizona ranks 14th in EPA per play, with Kyler Murray sitting 10th in success rate and 12th in EPA per play among qualified quarterbacks. He hasn’t put up flashy stats, but the efficiency metrics suggest he’s in control.
This squad can compete with just about anyone in the league. The real question: can they finish the job against superior opponents like San Francisco?
49ers vs Cardinals Pick: This game opened with San Francisco laying -3.5 and the total as high as 47.5. Now the line has dipped to -1.5, with the total sliding down to 44.5.
Oddly enough, I like the angle of backing a Mac Jones–led 49ers team under the key number of -3. I can’t believe I’m even typing that, but that’s the type of magic Kyle Shanahan is capable of manufacturing. I grabbed San Francisco at -2.5 earlier in the week, and now bettors can actually find an even better number across the market.
I think he can be just as productive as Purdy, given the talent surrounding him on both sides of the ball, along with Arizona&#8217;s knack for playing themselves out of games, especially against a team like San Francisco.
If Jones starts &#8211; that&#8217;s great, I’ll be satisfied. If it’s Purdy, then we can assume he’s close to 100%, and we were able to snag a much better number in the betting market than we should have.
Play: 49ers -2.5 (-110)
<h2>Still Didn&#8217;t Get Your NFL Fix?</h2>
<a href="https://x.com/dannyburke5" target="_blank" rel="noopener">Follow me on X @dannyburke5</a> for all my picks, analysis and plenty more. Also be sure to <a href="https://twitter.com/YourBettingNews" target="_blank" rel="noopener">follow Betting News on ‘X’ </a>and <a href="https://www.twitch.tv/bettingnews" target="_blank" rel="noopener">Twitch</a> to catch us on stream! Betting News is also on <a href="https://www.tiktok.com/@yourbettingnews" target="_blank" rel="noopener">TikTok!</a> Follow us for more picks and news every day and check out our <a href="/picks/" target="_blank" rel="noopener">Free Expert Picks</a> for every major sports league.
<div class="my-3 card card-body d-flex flex-column flex-lg-row align-items-center" style="background-color: #01337d;">
 <div class="py-3 flex-fill">
 
 Get FREE Picks and Props Weekly
 
 Sign up for
 
 THE WEEKENDER NEWSLETTER
 
 </div>
 <div>
 <a class="mx-2 btn btn-lg btn-danger stretched-link text-nowrap" role="button" href="/newsletter-subscription/" style="padding: .5rem 2rem;width: 300px;margin: 0;">Get FREE Picks</a>
 </div>
</div>
<h2>Check Out All of Our Betting Resources at Betting News</h2>
<div class="p-rich_text_section">
<div class="su-list mb-5" style="margin-left:0px">
</div>
<ul class="p-rich_text_list p-rich_text_list__bullet" data-stringify-type="unordered-list" data-indent="0" data-border="0">
<li data-stringify-indent="0" data-stringify-border="0"><a class="c-link" href="/nfl/picks/" target="_blank" rel="noopener noreferrer" data-stringify-link="/nfl/picks/" data-sk="tooltip_parent">Picks &amp; Odds for the NFL</a></li>
<li data-stringify-indent="0" data-stringify-border="0"><a class="c-link" href="/nfl-betting-guide/" target="_blank" rel="noopener noreferrer" data-stringify-link="/nfl-betting-guide/" data-sk="tooltip_parent">NFL Betting Guide for Beginners</a></li>
<li data-stringify-indent="0" data-stringify-border="0"><a class="c-link" href="/ncaaf/picks/" target="_blank" rel="noopener noreferrer" data-stringify-link="/ncaaf/picks/" data-sk="tooltip_parent">Pick &amp; Odds for NCAAF</a></li>
<li data-stringify-indent="0" data-stringify-border="0"><a class="c-link" href="/guides/college-football-betting-guide/" target="_blank" rel="noopener noreferrer" data-stringify-link="/guides/college-football-betting-guide/" data-sk="tooltip_parent">NCAAF Betting Guide for Beginners</a></li>
<li data-stringify-indent="0" data-stringify-border="0"><a class="c-link" href="/mlb/picks/" target="_blank" rel="noopener noreferrer" data-stringify-link="/mlb/picks/" data-sk="tooltip_parent">Picks &amp; Odds in the MLB</a></li>
<li data-stringify-indent="0" data-stringify-border="0"><a class="c-link" href="/guides/mlb-betting-guide/" target="_blank" rel="noopener noreferrer" data-stringify-link="/guides/mlb-betting-guide/" data-sk="tooltip_parent">MLB Betting Guide for Beginners</a></li>
<li data-stringify-indent="0" data-stringify-border="0"><a class="c-link" href="/nba/picks/" target="_blank" rel="noopener noreferrer" data-stringify-link="/nba/picks/" data-sk="tooltip_parent">Picks &amp; Odds in the NBA</a></li>
<li data-stringify-indent="0" data-stringify-border="0"><a class="c-link" href="/guides/nba-betting-guide/" target="_blank" rel="noopener noreferrer" data-stringify-link="/guides/nba-betting-guide/" data-sk="tooltip_parent">NBA Betting Guide for Beginners</a></li>
<li data-stringify-indent="0" data-stringify-border="0"><a class="c-link" href="/nhl/picks/" target="_blank" rel="noopener noreferrer" data-stringify-link="/nhl/picks/" data-sk="tooltip_parent">Picks &amp; Odds in the NHL</a></li>
<li data-stringify-indent="0" data-stringify-border="0"><a class="c-link" href="/sports-betting-guides/nhl-betting-guide/" target="_blank" rel="noopener noreferrer" data-stringify-link="/guides/nhl-betting-guide/" data-sk="tooltip_parent">NHL Betting Guide for Beginners</a></li>
</ul>
</div>

NFL Week 7 Matchups & Prop Watch: Big Numbers for Burrow in Baltimore and Domination in the Desert for 7-0 Cardinals

San Francisco 49ers vs Arizona Cardinals (9/21): Is the Mac Attack Back?

Colts vs. Jaguars | NFL Week 14 Breakdown & Best Bets: Divisional Battle in the South

The top spot in the AFC North is up for grabs. Here's what you should expect in our Baltimore Ravens vs Pittsburgh Steelers preview & picks.

Baltimore Ravens vs Pittsburgh Steelers Preview & Predictions (11/7) | Knockin’ for the North

Get ready for this huge AFC showdown with our Buffalo Bills vs Cincinnati Bengals preview and picks in NFL Week 14.

Buffalo Bills vs Cincinnati Bengals Preview & Picks (12/7): Will Burrow get Buried?

Get all the info and action you need with our Detroit Lions vs Dallas Cowboys Thursday Night Football preview and picks.

San Francisco 49ers vs Arizona Cardinals (9/21): Is the Mac Attack Back?

Danny Burke

More NFL News

Colts vs. Jaguars | NFL Week 14 Breakdown & Best Bets: Divisional Battle in the South

Baltimore Ravens vs Pittsburgh Steelers Preview & Predictions (11/7) | Knockin’ for the North

Buffalo Bills vs Cincinnati Bengals Preview & Picks (12/7): Will Burrow get Buried?

Detroit Lions vs Dallas Cowboys Thursday Night Football Preview & Picks (12/4)

Giants vs. Patriots | NFL Week 13 Breakdown & Best Bets: Monday Night @ Foxborough