<p>The spatial spread of Mpox is influenced by human mobility, contact patterns, and zoonotic spillover. However, the mechanisms that drive the formation and persistence of localized hotspots remain poorly understood. In this study, we develop a network-based reaction–diffusion model that integrates adaptive human mobility, heterogeneous transmission, and spatially varying spillover. We first establish key analytical properties of the model, including positivity, boundedness, and a network-based basic reproduction number. Our analysis shows that mobility adapts to infection prevalence, effectively modifying diffusion across the network. As prevalence increases, mobility is reduced, limiting spatial spread regardless of epidemic timing. Numerical simulations reveal that, unlike classical models with constant diffusion, prevalence-dependent mobility slows spatial invasion, suppresses diffusion-driven instability, and promotes persistent localized hotspots. Higher-order transmission amplifies local outbreaks without changing invasion thresholds, while heterogeneous spillover increases transient infection levels but does not sustain spatial instability. Overall, the results demonstrate that feedback between infection prevalence and human mobility plays a central role in shaping spatial Mpox dynamics. The proposed framework provides a mechanistic explanation for persistent spatial heterogeneity and localized endemicity in connected populations.</p>