Dan Johnson takes you through his preview, prediction, and pick for NFL Week 3’s game between the San Francisco 49ers and the Arizona Cardinals on Sunday.

Levi’s Stadium hosts a divisional collision layered in urgency and memory. San Francisco has owned stretches of this rivalry, but Arizona swept the 49ers last season, including a comeback win in Santa Clara where Kyler Murray flashed both speed and touch. Now both teams arrive 2-0, still imperfect, but positioned for control of the NFC West. The line sits San Francisco −2.5 with a total of 44.5, signaling razor-thin margins in a matchup shaped by injuries and quarterback clarity. Below is my prediction for NFL Week 3’s game between the San Francisco 49ers and the Arizona Cardinals.

Here’s how I’ll play it. I’ll be pumping out these predictions for individual games all season, with plenty of coverage here on DraftKings Network. Follow my handle @dansby_edits for more betting plays.

Mac Jones carries the story and the offense for San Francisco. In his debut start, he threw for 279 yards, three touchdowns, no interceptions, completing 66.7% of passes and posting a passer rating of 113.1. He kept rhythm despite being sacked three times, hitting Jauan Jennings for 89 yards and a score and using Christian McCaffrey as an underneath outlet (15 receptions, 125 yards, one touchdown through two games). The 49ers average 266.0 passing yards per game, ranking fifth in the league, but their run game has stalled at 98.0 yards per contest, with McCaffrey stuck on 3.5 yards per carry and still searching for his first rushing touchdown. Ricky Pearsall has stretched fields with 164 yards on eight receptions, averaging 20.5 yards per catch, keeping defenses honest even without Brandon Aiyuk or George Kittle.

San Francisco’s defense remains its ballast. They allow 17.0 points per game (seventh) and just 166.0 passing yards per game (sixth), even with Nick Bosa still revving into form. Bosa has 15 tackles, four tackles for loss, and two sacks, while Fred Warner leads the team with 19 tackles and two tackles for loss. Dee Winters and Marques Sigle have fortified depth, and San Francisco has surrendered only 1 rushing touchdown through two weeks. Their third-down defense sits at 33.3% allowed, a top-six mark, forcing opponents to finish drives through contested throws.

Arizona’s identity starts with Murray. He has completed 70.4% of passes, thrown for 383 yards, three touchdowns, one interception, and added 70 rushing yards. His improvisation erased deficits last year against San Francisco, and his passer rating sits at 100.8. Rookie Marvin Harrison Jr. has flashed with seven catches for 98 yards and a touchdown, while Trey McBride is the safety blanket with 12 receptions for 139 yards on 16 targets. James Conner and Trey Benson split carries, with Conner producing 73 rushing yards and two total touchdowns, and Benson hitting chunk gains at 7.5 yards per attempt. Yet Arizona’s passing offense still ranks just 27th at 170.5 yards per game, and they’ve taken six sacks in two contests.

Defensively, Arizona has shown balance but cracks. They allow 17.5 points per game (10th) and a stingy 78.0 rushing yards per game (6th), but their secondary leaks with 255.5 passing yards allowed per game (26th). Budda Baker leads with 18 tackles, Calais Campbell anchors with two sacks, and Baron Browning adds an interception. Injuries at cornerback stretch depth: Garrett Williams is out, and both Max Melton and Will Johnson are questionable, leaving rookies like Denzel Burke exposed against NFL tempo. Against a 49ers offense where three different receivers have already topped 70 yards in a game, that mismatch looms.

Cardinals vs. 49ers pick, best bet

The counterarguments lean on Arizona’s steadiness. Murray’s 61.4% defensive completion rate allowed suggests his defense forces checkdowns, and his own 32 rushing yards per road game extend drives. Arizona has covered nine of its last 13 games and enters with discipline: just one turnover in two games and a 100% fourth-down conversion rate. Meanwhile, San Francisco is 4-12 ATS in its last 16 home games, suggesting public money often overrates Levi’s Stadium edges. If McCaffrey’s rushing inefficiency continues and Jones is forced into high-volume attempts against disguised coverages, the Cardinals’ balanced script stays live.

But situational layers favor San Francisco. Clean weather in the 70s with light winds erases external noise. The 49ers are 7-2 straight up in September across their last nine, and Kyle Shanahan has schemed red-zone efficiency at 57.1%, balancing Jones’ accuracy with compressed formations. Arizona, by contrast, nearly collapsed against Carolina, blowing a 24-point lead before surviving late. That fragility underscores what happens when Murray’s off-script magic stalls.

Christian McCaffrey’s dual-threat usage against a defense allowing 3.8 yards per carry should generate conversion after conversion. Ricky Pearsall’s vertical game will stretch an already depleted corner unit. Kyler Murray’s off-schedule playmaking will keep Arizona alive, but Nick Bosa’s edge pressure will squeeze him into hurried windows. The defense’s efficiency against Murray’s limited passing attack, combined with Jones’ rhythm passing against a ravaged secondary, tilts this NFC West opener toward the home side. We’ll lay the points with the Niners.

Final Score: 49ers 26, Cardinals 20.

Best bet: 49ers -2.5 (-105) vs. Cardinals

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For a prop lean, Christian McCaffrey over 5.5 receptions. McCaffrey’s receiving floor is already baked into San Francisco’s offense. Through two games he’s logged 15 catches for 125 yards and a touchdown, averaging 7.5 receptions per game on 11 targets. That’s not gadget usage—it’s core design. Kyle Shanahan builds option routes, angle screens, and swing passes to counter heavy fronts, and Arizona’s defense forces that script. The Cardinals allow only 78.0 rushing yards per game (sixth) on 3.8 yards per carry, but they’re far more vulnerable through the air, giving up 255.5 passing yards per game (26th). That tilt naturally pushes touches toward McCaffrey in space. Mac Jones leaned on him repeatedly in his debut, and with Brandon Aiyuk and George Kittle absent, the short game becomes the extension of the run. Expect 6–8 targets, 5–7 receptions, and 40–50 receiving yards. The floor is insulated by scheme, and the matchup raises the ceiling.

Best prop lean: Christian McCaffrey o5.5 receptions (+125)

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