The Week 11 NFC West battle between the San Francisco 49ers and the Arizona Cardinals on November 16, 2025, at State Farm Stadium highlights two teams with vastly different expectations yet equally important motivations. The 49ers, firmly entrenched as one of the NFC’s elite, enter this matchup looking to maintain their divisional dominance and sharpen their rhythm for the playoff push, while the Cardinals are hoping to play spoiler and continue showing progress under their rebuilding phase. San Francisco has once again established itself as one of the league’s most balanced and efficient teams under head coach Kyle Shanahan, whose offensive creativity and adaptability remain unmatched. Quarterback Brock Purdy continues to operate the offense with remarkable precision and composure, consistently making the right reads and maximizing yards after the catch through San Francisco’s versatile playmakers. Christian McCaffrey remains the engine of the offense, his dual-threat ability forcing defenses to stay honest on every snap. Alongside him, Deebo Samuel and Brandon Aiyuk provide matchup nightmares with their combination of speed, physicality, and route discipline, while tight end George Kittle’s versatility as both a blocker and receiver gives the 49ers flexibility to attack from multiple formations. Expect Shanahan to lean heavily on misdirection, motion, and quick-developing plays to neutralize Arizona’s defensive front. The 49ers’ offensive line, anchored by Trent Williams, continues to protect Purdy effectively and open consistent running lanes, allowing the team to control time of possession — a key factor against any divisional opponent. Defensively, San Francisco remains a powerhouse under coordinator Steve Wilks, boasting one of the league’s deepest front sevens led by Nick Bosa, Javon Hargrave, and Fred Warner. Their pass rush, combined with excellent gap discipline, has made it difficult for opponents to establish rhythm, while the secondary — featuring Charvarius Ward and Talanoa Hufanga — has tightened coverage and eliminated explosive plays.

Against Arizona, the 49ers’ defense will focus on containment, especially limiting quarterback Kyler Murray’s ability to extend plays with his legs. Murray’s mobility remains Arizona’s biggest threat, and San Francisco will likely rely on spy packages and edge discipline to neutralize scrambles and off-script throws. The Cardinals, though still a work in progress, have shown signs of improvement under head coach Jonathan Gannon, particularly in effort, discipline, and offensive creativity. Running back James Conner anchors their ground game with physicality, while rookie wideout Marvin Harrison Jr. has brought a much-needed spark to the passing attack, instantly becoming Murray’s go-to target. However, Arizona’s offensive line remains a liability, and facing San Francisco’s relentless front could prove overwhelming. Defensively, the Cardinals have battled hard despite lacking star power, with linebacker Zaven Collins and safety Budda Baker leading a unit that plays fast but often bends under pressure against high-powered attacks. Expect Gannon to mix coverages and blitzes in an attempt to disrupt Purdy’s timing, but the 49ers’ offensive precision may prove too much for a defense still finding its footing. From a betting perspective, San Francisco enters with a 5-4 ATS record, reflecting a team that wins consistently but doesn’t always cover large spreads, while Arizona’s 5-3 ATS mark indicates they’ve been scrappy and often exceed market expectations. The 49ers have dominated recent meetings, yet divisional familiarity tends to tighten the margins. For Arizona to stay competitive, they must protect Murray, win the turnover battle, and capitalize on red-zone opportunities — all areas that have plagued them throughout the season. If San Francisco controls the clock, pressures Murray into hurried decisions, and executes its game plan cleanly, this should result in a decisive win that reinforces their NFC supremacy. However, if the Cardinals’ defense can create chaos early and the offense finds rhythm through quick passes and designed runs, they have the potential to make this game closer than the spread suggests. Ultimately, the 49ers’ balance, experience, and talent across all phases make them the clear favorite to handle business and continue their march toward another deep postseason run.