Irrigated agriculture is a key activity for the long-term survival of human-environmental systems and the assessment of agricultural sustainability has been gaining increasing relevance. In spite of several proposals developed, there is not a holistic approach that can be generally applied to assess sustainability of irrigated agricultural areas. In this paper we present a framework and associated indicators for the assessment of sustainability of irrigated agricultural systems in different contexts and locations. The framework covers four main sustainability dimensions: environmental integrity, economic resilience and profitability, social wellbeing and good governance. This approach was tested in 10 agricultural areas in eight different countries that represent a wide variety of situations in terms of agricultural development, environmental conditions, socio-economic settings and political contexts, but that share the fact that water use is a critical aspect for agricultural development. The obtained results illustrate the usefulness of the proposed framework to obtain a holistic picture of sustainability in irrigated agriculture areas, even in situations of poor data availability. It is also an excellent starting point for the construction of roadmaps towards more sustainable agricultural systems.