Simultaneous removal of nitrogen and phosphorous is a recommended practice while treating wastewater. In the present study, control strategies based on proportional-integral (PI), model predictive control (MPC), and fuzzy logic are developed and implemented on a plant-wide wastewater treatment plant. Four combinations of control frameworks are developed in order to reduce the operational cost and improve the effluent quality. As a working platform, a Benchmark simulation model (BSM2-P) is used. A default control framework with PI controllers is used to control nitrate and dissolved oxygen (DO) by manipulating the internal recycle and oxygen mass transfer coefficient (KLa). Hierarchical control topology is proposed in which a lower-level control framework with PI controllers is implemented to DO in the sixth reactor by regulating the KLa of the fifth, sixth, and seventh reactors, and fuzzy and MPC are used at the supervisory level. This supervisory level considers the ammonia in the last aerobic reactor as a feedback signal to alter the DO set-points. PI-fuzzy showed improved effluent quality by 21.1%, total phosphorus removal rate by 33.3% with an increase of operational cost, and a slight increase in the production rates of greenhouse gases. In all the control design frameworks, a trade-off is observed between operational cost and effluent quality.