The September 25, 2025 matchup between the Seattle Seahawks and the Arizona Cardinals in Glendale carries heavy divisional weight early in the season, as both teams look to establish footing in the competitive NFC West while dealing with very different circumstances. Seattle enters the game with momentum and roster stability, having shown resilience in road contests and covering spreads consistently when traveling, a trend that bettors have noticed. Their formula has been balanced offensive execution—running the ball early to establish tempo and then using play-action to exploit mismatches in the secondary—combined with a defense that thrives on opportunistic turnovers and well-timed pressure. On the other side, Arizona finds itself in a more precarious position, having just lost running back James Conner to a season-ending ankle injury, a blow that reshapes their offensive identity and forces quarterback Kyler Murray to shoulder even more of the workload. Without a reliable ground game, the Cardinals risk becoming one-dimensional, relying on Murray’s arm and mobility to move the chains, which opens the door for Seattle’s defense to dial up pressures, disguise coverages, and attack the pocket to force hurried decisions.

Arizona’s receiving corps will need to step up, winning their matchups and creating separation quickly if the Cardinals hope to sustain drives and keep their defense off the field. Defensively, the Cardinals must find a way to contain Seattle’s rushing attack and prevent chunk plays off play-action, but their inconsistency against physical offensive lines has been an ongoing issue. For Seattle, the task is straightforward: protect the quarterback, lean on their backs to control clock and tempo, and trust their defense to limit Murray’s big-play potential. Special teams could also prove decisive in what may be a closer battle than the rosters suggest, with field position and kicking reliability playing major roles. From a betting standpoint, Seattle’s strong track record against the spread on the road—particularly in divisional matchups—gives them an edge, while Arizona’s 1–5 ATS record in recent home underdog situations underscores their struggles to meet expectations at State Farm Stadium. The total is likely to hover around the mid-40s, and with Arizona’s offense hampered by the loss of Conner, the under may hold more appeal unless Murray can deliver an exceptional performance. Ultimately, this game looks like a test of Seattle’s ability to capitalize on an opponent’s adversity and Arizona’s capacity to rally behind its star quarterback to prove they can still compete, but unless the Cardinals’ defense creates turnovers and Murray produces magic, the Seahawks appear better positioned to leave Glendale with a critical divisional win.