Critical barriers to safe and secure drinking water may include sources (e.g. groundwater contamination), treatments (e.g. treatment plants not properly operating) and/or contamination within the distribution system (infrastructure not properly maintained). The performance assessment of these systems, based on monitoring, process parameter control and experimental tests, is a viable tool for the process optimization and water quality control. The aim of this study was to define a procedure for evaluating the performance of full-scale drinking water treatment plants (DWTPs) and for defining optimal solutions for plant upgrading in order to optimize operation. The protocol is composed of four main phases (routine and intensive monitoring programmes - Phases 1 and 2; experimental studies - Phase 3; plant upgrade and optimization - Phase 4). The protocol suggested in this study was tested in a full-scale DWTP placed in the North of Italy (Mortara, Pavia). The results outline some critical aspects of the plant operation and permit the identification of feasible solutions for the DWTP upgrading in order to optimize water treatment operation.