This paper presents the development of a generally applicable method for the layout optimization of coastal cage aquaculture systems in Southeast Asia. The method combines data from the authors’ spatial-planning methodology with results of water quality modelling and an optimization technique based on genetic algorithms. The effectiveness of the method is successfully demonstrated for a target aquaculture site in northwest Bali, Indonesia. Optimum siting and sizes of fish farms to maximize fish production and promote fish growth while securing environmental sustainability are delivered for the site in Bali. The results of the application to the western channel of the site show that by proper fish farming layout, environmentally sustainable fish production in the site in Bali could rise tremendously with respect to the current operating conditions. It is found that installing many smaller fish farms than fewer larger farms on the western tidal channel of the aquaculture site is much more profitable. The method has broad applicability and can be upscaled to new sites, and for assessment, expansion, and optimization of the currently operating sites.