The main issue of this paper is the design of a class of SISO robust control law for the regulation of dissolved oxygen (DO) of an industrial Activated Sludge Wastewater Plant via the air flow rate (non-affine control input). The control design is related with an uncertainty estimator (reduced order observer) based Generic Model Control (GMC). The desired dissolved oxygen trajectory is proposed as a Proportional-Integral (PI) form of the regulation error and the modeling error related with the respiration rate and the oxygen mass transfer coefficient are on-line estimated with a reduced order observer, these structures produce a feedback/feed forward regulator which is robust against model uncertainties and disturbances. The system’s closed-loop behavior is analyzed via the estimation error and regulation error dynamics. The performance of the proposed control law is illustrated with numerical simulations, comparing the proposed controller with a well-tuned PI controller.