Fusegates present a reliable and cost-effective alternative, which increase flood protection and water supply benefits. This article develops a comprehensive simulation–optimization framework for practical selection, installation, and operation of fusegates. The computational model simulates the complicated hydraulic behavior of fusegates systems with varying design characteristics and consequential anomalous routing process in case of flood events. An efficient mixed genetic algorithm (GA) is subsequently developed and coupled with the highly nonlinear hydraulic simulation model to minimize the overall expected annual cost under structural, hydraulic, and operational constraints. Types, heights, and tipping heads of gates are explicitly treated as optimization decision variables. Furthermore, the frequent practice of installing all gates in the same level is practically improved to favorably help minimize water loss in case of moderate discharge floods. The proposed model is demonstrated and discussed for a case study of the Taleghan Dam fusegates installation project in Iran. A series of sensitivity analyses are also conducted to assess routing effect and uncertainty in water unit price and replacement costs and provide more insight and understanding of the design problem.