Water shortages have led to the widespread adoption of adaptive measures in south-eastern Spain irrigated agriculture, with an emphasis on large-scale supply with desalinated seawater (DSW). This study develops an analytical and integrated perspective on the use of desalination as a water source for crop irrigation since the mid-2000s in the Segura River Basin (SRB), identifying its strengths and current limitations. The analysis describes the development of agricultural DSW supply as a pivotal means to securing crop production in the SRB, addressing the key questions for its sustainable implementation, including: (1) the main agronomic concerns, such as low nutrients concentration, crop toxicity risk due to high specific ions concentration, or the sodicity risk affecting soil physical properties; (2) the energy consumption for DSW production and allocation, together with the associated greenhouse gas emissions and their effect on the crops' carbon footprint; and (3) the production and allocation cost, as the main limiting factor for its general adoption since at the moment it jeopardises the profitability of the most representative crops. This case study evidences that DSW can be a supplementary supply contributing to effectively remove the hydrological constraints for crop production in the SRB.