<p>Urban centers are critical nexuses where climate, environmental exposures, and socioeconomic disparities converge to shape infectious disease dynamics. Addressing the underexploration of these compound drivers, we conducted a comparative longitudinal analysis across three major Chinese cities, integrating multi-dimensional epidemiological, climatic, air quality, and socioeconomic data. Our framework incorporated Spearman’s correlation, mutual information networks, principal component analysis, and time-series visualization. Results demonstrated that the efficacy of non-pharmaceutical interventions against Omicron varied inversely with population density: highest in Chongqing, moderate in Shanghai, and lowest in Hong Kong. Furthermore, correlation matrices revealed distinct city-specific patterns; notably, hand, foot, and mouth disease in Shanghai correlated with passenger volume (<i>ρ</i> = 0.64) and international tourists (<i>ρ</i> = 0.45), whereas these associations were attenuated in Chongqing. Mutual information networks uncover non-monotonic synergies and hidden city-specific hubs (e.g., NO₂, SO₂) missed by correlation, alongside shared socioeconomic hubs like passenger volume and containment. Composite indices captured systemic co-exposures, with the crowd-gathering index correlating with scarlatina (<i>ρ</i> = 0.37) and dengue (<i>ρ</i> = 0.35). Collectively, these findings indicate that urban infection risks originate from complex, context-dependent systems. Consequently, we propose a planetary health-based urban governance framework with six pillars: intelligent foresight, nature-based design, collaborative governance, medical preparedness, data integration, and global solidarity, fostering enhanced urban resilience.</p>