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Background The European Environment Agency estimates that 75% of the European population lives in cities. Despite the many advantages of city life, the risks and challenges to health arising from urbanization need to be addressed to tackle the growing burden of disease and health inequalities in the cities. This article presents the study protocol of the Urban Environment and Health: a cross-sectional multiregional project based on Population Health Surveys in Spain (DAS-EP project), that aims to investigate the complex association between the urban environmental exposures (UrbEE) and health. Methods DAS-EP is a Spanish multiregional cross-sectional project that combines Population Health Surveys (PHS) and Geographical Information System (GIS) allowing to collect rich individual level data from 17,000 adult citizens participating in the PHS conducted in the autonomous communities of the Basque Country and Andalusia, the Valencian Community, and the city of Barcelona in years 2021–2023. This study focuses on the population living in cities or metropolitan areas with more than 100,000 inhabitants. UrbEE are described by objective estimates at participants’ home addresses by GIS and subjective indicators present in PHS. The health outcomes included in the PHS and selected for this study are self-perceived health (general and mental), prevalence of chronic mental disorders, health-related quality of life, consumption of medication for common mental disorders, and sleep quality. We aim to further understand the direct and indirect effect between UrbEE and health as well as to estimate the impact at the population level taking respondents’ socio-demographic and socio-economic characteristics, and lifestyle into account. Discussion This study is a clear commitment to the generation of urban environment indicators within the field of public health with a health equity perspective. The results will be novel for the inclusion of objective & subjective UrbEE as well as the combination of PHS from different study areas and GIS estimates. This methodological approach will provide a large volume of information and a large sample size of the study. The results will ultimately help identify urban indicators, increasing the capacity to detect and intervene in community health, improving the routine surveillance and monitoring of the cities’ health information systems.