The circulating cooling water system is widely used in various industrial production fields, and its operating cost largely depends on external factors, such as ambient temperature and working medium flow. Considering the relative elevation of the heat exchanger, this study establishes a total system operation cost analysis and optimization model based on the superstructure method. The model uses ambient dry bulb temperature, ambient wet bulb temperature, and working medium flow as random variables. Water supply temperature is adopted as the decision variable, and the minimum operating cost of the system is used as the objective function. An analysis of the effect of the three random variables on the operation cost shows that the effect of ambient dry bulb temperature on the operation cost is negligible, and the effect of ambient wet bulb temperature and working medium flow on the operation cost is significant. In addition, a control equation of water supply temperature is established to determine the “near optimal” operation, which is based on the correlation among ambient wet bulb temperature, working medium flow, and optimal water supply temperature. Then, the method is applied to a case system. The operating cost of the system is reduced by 22–31% at different times during the sampling day.