The influence of aeration diffuser system design on electricity usage, effluent water quality, and life-cycle cost in biological wastewater treatment was investigated. A plant-wide model was implemented, and simulations were carried out with different process configurations and aeration systems. Model-aided design of new aeration diffuser systems could significantly decrease electricity usage and life-cycle cost while at the same time avoiding negative effects on the treatment performance. The optimum distribution of diffuser systems in tanks in series was found to be influenced by process configuration, volumetric loading rate, temperature, and the internal recirculation flow rate. Compared with a conventional design approach, increasing the number of diffusers, up to a critical point, led to higher energy efficiency and lower life-cycle cost. This was despite an increasing limitation of the minimum airflow rate, leading to dissolved oxygen levels significantly exceeding control targets. Aeration systems optimized by simulations were found to, independently of process configuration, exhibit 20% lower electricity usage and 16%-18% lower life-cycle costs compared with systems designed based on a more conventional approach typically applied in practice.