An unconventional cascade control system, for the regulation of air supply in activated sludge wastewater treatment plants (WWTPs), was tested. The dissolved oxygen (DO) set point in the aeration tank was dynamically calculated based on effluent ammonia concentration, following a fuzzy logic based approach. First, simulations were conducted, according to the BSM2 protocol, for a general comparison with more conventional control strategies. It turned out that the effluent quality could be improved by 7–8%, based on the EQI parameter. Moreover, the aeration energy requirement could be reduced up to 13%. Subsequently, the system was installed in a full-scale WWTP. While stably complying with the ammonia effluent standard (10 mg/L), excess air supply was prevented, and a reduction of the specific power consumption (kWh/kgCODremoved) of 40–50% was recorded with respect to the previously installed PID controller (fixed DO set point).