Aim: Polypharmacy, defined as the concurrent use of multiple medications, poses significant health risks, particularly among aging populations. While polypharmacy is a recognized concern, limited research has investigated its spatial distribution or the demographic and socioeconomic factors influencing its prevalence. This study aimed to examine the spatial patterns of polypharmacy across Japan and identify regional characteristics associated with higher polypharmacy rates. Methods: An ecological study was conducted across 335 local health units in Japan using data from national health, demographic, and geographic databases. Polypharmacy was defined as prescriptions containing seven or more drugs, and the standardized polypharmacy ratio (SPR) was calculated by age-group population. Spatial autocorrelation of SPR was assessed using Moran’s I statistic. Clustering analysis incorporating SPR and regional variables identified distinct high-risk areas. Results: The prediction model for polypharmacy prescriptions achieved an R² of 0.98, indicating high accuracy, though SPR remained heterogeneous. Significant spatial autocorrelation was observed for both polypharmacy prescriptions (Moran’s I = 0.4; P < 0.001) and SPR (Moran’s I = 0.24; P < 0.001), highlighting regional clustering. Clustering analysis identified four groups by polypharmacy risk (Critical, High, Moderate, and Low). High-SPR areas were associated with higher population density, a greater proportion of younger adults (ages 20–60), and increased levels of education, income, and tertiary industry workers. Conclusion: Polypharmacy in Japan exhibits significant spatial clustering, with higher rates in urbanized regions driven by demographic and socioeconomic factors. Region-specific interventions addressing these unique characteristics are essential for improving polypharmacy management.