This paper develops a framework for the identification, assessment and analysis of the water reuse-carbon-energy-food-climatic (WEFC) nexus in an integrated peri-urban wastewater treatment and reuse system. This methodology was applied to the municipal wastewater treatment plant (WWTP) of Peschiera Borromeo (Milan, Italy) and its peri-urban district to define the most possible affirmations and conflicts following the EU regulations 741/2020. Results of this work showed that transferring the WEFC nexus from theory to practice can realize sustainable resource management in the operating environment by providing a reduction in greenhouse gas (GHG) emissions, overall energy savings, reduction in water stress and optimization of agricultural practices. Particularly, it was found that if the plant configuration is upgraded to reach water quality class C for water reuse, instead of wastewater discharge, energy savings are estimated to reach up to 7.1% and carbon emissions are supposed to be reduced up to 2.7%. In addition, enhancing water quality from class C to class A resulted in increments in energy and carbon footprint of 5.7% and 1.7%, respectively. Nevertheless, higher quality crops can be cultivated with reclaimed water in class A, with bigger economic revenues and high recovery of nutrients (e.g., recovery of 154,450 kg N/y for tomato cultivation).