Multi-objective performance assessment of operational strategies at wastewater treatment plants (WWTPs) is a challenging task. The holistic perspective applied to evaluation of modern WWTPs, including not only effluent quality but also resource efficiency and recovery, global environmental impact and operational cost calls for assessment methods including both on- and off-site effects. In this study, a method combining dynamic process models – including greenhouse gas (GHG), detailed energy models and operational cost – and life cycle assessment (LCA) was developed. The method was applied and calibrated to a large Swedish WWTP. In a performance assessment study, changing the operational strategy to chemically enhanced primary treatment was evaluated. The results show that the primary objectives, to enhance bio-methane production and reduce GHG emissions were reached. Bio-methane production increased by 14% and the global warming potential decreased by 28%. However, due to increased consumption of chemicals, the operational cost increased by 87% and the LCA revealed that the abiotic depletion of elements and fossil resources increased by 77 and 305%, respectively. The results emphasize the importance of using plant-wide mechanistic models and life cycle analysis to capture both the dynamics of the plant and the potential environmental impacts.