Delta regions are compound socio-ecological systems increasingly exposed to various multi hazards (e.g., drought, flooding). The Danube Delta, one of the most complex wetland areas in Europe, and one of the most vulnerable regions when it comes to drought, defined by its key vulnerable categories: women, children, the elderly population, the unemployed etc. In addition to the demographic aspects, there is also the infrastructure that puts a damper on the development of certain sectors of the economy, be they technical (water, gas, electricity), or social (schools, medicine, medical facilities). The current paper aims to apply a multi-criteria regional level aridity and drought vulnerability assessment relying on both quantitative and qualitative methods in attaining a two-fold objective: (1) developing a comprehensive socio-economic aridity and drought vulnerability index in order to (2) identifying aridity and drought-vulnerable areas based on the finest indicators available for quantifying socio-economic vulnerability. The main research findings point to a general high and very high socio-economic vulnerability in the central and northern parts of the Danube Delta (36.3% of the total population) because of the high values of the elderly population, of households not connected to the water supply and sewage network, of the economic dependency rate, the high distance from the polarizing centres and the small numbers of emergency situation units. The low and very low vulnerability is registered in the West and in Sulina town (19.4% of the total population) where the accessibility to infrastructure and services makes up for the overall high drought exposure (dry/arid and semiarid climate). The research findings will improve the general understanding of drought vulnerability in a deltaic area, thus providing valuable information to be used by policymakers for drought management.