The World Health Organization endorses the study of diseases from the perspective of the Determinants of Health (DH), that is, the circumstances in which people are born and raised, the environment in which they grow up and age and their lifestyle. The aim of this study is to analyze the spatial behavior of the prevalence of asthma in Aragon, a Mediterranean region in Spain, under the DH approach. The methodological process entailed building a spatial database collating asthma prevalence as dependent variable, and lifestyle, socioeconomic, and climate indicators as explanatory factors, and then evaluating the spatial variability of the relationships by combining the Principal Component Analysis (PCA), Multiscale Geographically Weighted Regression (MGWR) models and cartographic design techniques. MGWR evidenced spatially varying relationships operating at different scales. Lifestyles seem closely tied to the prevalence of asthma in most of the study area while urban functionality and local climate patterns seem to boost prevalence rates in some specific enclaves. Consequently, the social and environmental conditions that characterize the study area translate into several DH scenarios modulating the spatial distribution of asthma. This differential DH behavior detected by local regression models is relevant to guiding and refining public health decision‐making.