This paper presents a nonlinear control approach for a simplified activated sludge model that covers the reduction of biodegradable substrate in biological wastewater treatment. In the proposed control scheme, the volume flow of oxygen into the aeration tank and the volume flow of excess sludge out of the settler tank are utilized as manipulated variables. As the oxygen concentration as well as the substrate concentration represent flat outputs, the proposed control strategy takes advantage of differential flatness. The inverse dynamics is evaluated in a feedforward manner using only desired values from a trajectory planning module in combination with stabilizing proportional-integral feedback of the substrate concentration as well as the oxygen concentration, respectively. Consequently, accurate tracking of desired trajectories for the flat outputs becomes possible without cost-intensive and often unreliable measurements of the bacteria concentration. As shown by simulation results, steady-state accuracy concerning the substrate concentration is guaranteed due to the integral control part despite dominant parameter uncertainties concerning the maximum growth rate of bacteria and variations of substrate concentration in the influent volume flow as disturbance. Hence, regulations on the admissible substrate concentration at the plant output can be easily met and plant operating costs can be significantly reduced resulting in superior plant efficiency.