Ambitious energy targets in the 2020 European climate and energy package have encouraged many stakeholders to explore and implement measures improving the energy efficiency of water and wastewater treatment facilities. Model-based process optimization can improve the energy efficiency of wastewater treatment plants (WWTP) with modest investment and a short payback period. However, such methods are not widely practiced due to the labor-intensive workload required for monitoring and data collection processes. This study offers a multi-step simulation-based methodology to evaluate and optimize the energy consumption of the largest Italian WWTP using limited, preliminary energy audit data. An integrated modeling platform linking wastewater treatment processes, energy demand, and production sub-models is developed. The model is calibrated using a stepwise procedure based on available data. Further, a scenario-based optimization approach is proposed to obtain the non-dominated and optimized performance of the WWTP. The results confirmed that up to 5000MWh annual energy saving in addition to improved effluent quality could be achieved in the studied case through operational changes only.