The objective of this paper is to complement the effluent quality (EQI) and operational cost (OCI) indices used to evaluate (plant-wide) control strategies in wastewater treatment systems with a new dimension dealing with greenhouse gas (GHG) emissions. The GHG evaluation is based on a set of comprehensive dynamic models that estimate the most significant potential on-site (secondary and sludge treatment, sludge disposal) and off-site (net energy use, embedded chemicals) sources of GHG emissions. The study presented here calculates and discusses the changes in the EQI, OCI and the formation of carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) as a consequence of varying four process variables: i) system aeration in the activated sludge section; ii) capture efficiency of particulates in the primary clarifier; iii) the temperature (T) regime in the anaerobic digester; and iv) the control of nitrogen rich returns coming from the sludge treatment. Simulation results show the undesirable effects that energy optimization might have on GHG production: Although off-site CO2 emissions may decrease, primarily as a result of: i) reduced aeration energy requirements; and/or ii) increased energy recovery from the sludge treatment, such effects might be counterbalanced by increased N2O emissions in the activated sludge plant due to the 300-fold stronger greenhouse effect of N2O than CO2. The reported results emphasize the importance of a plant-wide approach and the need to consider the interactions between the different treatment units when evaluating the global warming potential (GWP) of a wastewater treatment plant.