The sustainability in a river with respect to water quality is critical because it is highly related with environmental pollution, economic expenditure, and public health. This study proposes a sustainability problem of wastewater treatment system for river ecosystem conservation which helps the healthy survival of the aquatic biota and human beings. This study optimizes the design of a wastewater treatment system using the parameter-setting-free harmony search algorithm, which does not require the existing tedious value-setting process for algorithm parameters. The real-scale system has three different options of wastewater treatment, such as filtration, nitrification, and diverted irrigation (fertilization), as well as two existing treatment processes (settling and biological oxidation). The objective of this system design is to minimize life cycle costs, including initial construction costs of those treatment options, while satisfying minimal dissolved oxygen requirements in the river, maximal nitrate-nitrogen concentration in groundwater, and a minimal nitrogen requirement for crop farming. Results show that the proposed technique could successfully find solutions without requiring a tedious setting process.