The present work aimed at identifying the geographical variability, as well as the socioeconomic, lifestyle and environmental determinants of people’s health-related quality of life (HRQoL) at an aggregated level, and to investigate whether men’s and women’s HRQoL are affected differently by these characteristics. A cross-sectional spatial analysis in the context of the ATTICA epidemiological study. HRQoL data were provided by the ATTICA epidemiological study for n = 2749 participants with complete data for geographical identification, (n = 1375 women [44 years old (SD = 14 years)] and n = 1374 men [45 years old (SD = 13 years)]. Socio-economic, demographic, and environmental characteristics were obtained from official national and international databases. Poisson regression and Geographically Weighted Poisson regression analysis were used for the global and the local statistical modelling, respectively. Better HRQoL was detected in areas with higher socioeconomic status, with younger residents following healthier lifestyle and eating habits, higher percent of married individuals, lower percent of illiterate people and rate of immigration, as well as in municipalities with higher land coverage by green urban areas. A significant interaction between sex and studied area on HRQoL was observed, suggesting that men and women follow different patterns regarding their quality of life. In line with the current European policy developments, our findings support the transformation of public health actions to local authorities and provide input for policy makers to better understand how people’s HRQoL is affected by the characteristics of the area in which they live.