This study reports an up-to-date summary of the principal barriers still limiting reclaimed water use for agriculture in Italy, and particularly in Sicily. Moreover, it provides a geographic informative system (GIS)-based procedure for evaluating the potential treated wastewater (TW) reuse in the Sicilian region as a decision support system for its management. The survey, based on possible economic, morphologic, and design solutions, evidenced a feasible integration of several wastewater treatment plants (WWTPs) with irrigation areas, allowing the water availability enhancement. Overall, the potential volume of TW by WWTPs (connected to irrigation districts) is 163 × 106 m3 year−1, while the water deficit is 66 × 106 m3 year−1. The feasibility of TW reuse in Sicily was also analysed at the light of the World Health Organization microbial risk assessment. Escherichia coli (E. coli) analyses mostly accomplished these guidelines while conflicting with the restrictive Italian standards. Despite several limiting factors (restrictive legislations, high distance and unfavourable slope between WWTPs and irrigable areas, high monitoring and distribution costs) still hamper the exploitation of reclaimed water use in Sicilian agriculture, some solutions were identified to implement this practice.