This article presents the methodology and results of a pioneering investigation in the determination and mapping of socio-residential vulnerability in the city of Barcelona according to a multi-criteria synthetic analysis. The methodology followed is based on a system of indicators elaborated from the exploitation of habitual statistical Open Data complemented with specific unprecedented data elaborated and supplied by the Barcelona City Council. The analysis is based on secondary data and it is structured in georeferenced axes, components, and indicators, which allow determination of the sociodemographic, socioeconomic, and urban and residential space characteristics at neighborhood, population census unit, and urban block level. The objective of the research was to detect, determine, and establish a measure of differentiation relative to the degree of residential vulnerability of some neighborhoods with respect to others, in order to seek prioritization measures for action in the most vulnerable areas. The results of the research provide a series of maps that allow us to define the areas where the highest levels of vulnerability indicators coincide according to a synthetic multi-criteria analysis.