The efficiency and reliability of thermal power plant directly depends on conditions of the condensation-steam system. The key of energy-saving and optimal operation in condensation-steam system is to adjust the circulating cooling water flow with different operation conditions to get the optimal vacuum. This paper presents the optimal mathematical model of circulating water flow of a 600MW supercritical thermal power plant using Matlab/Simulink. And this model has comprehensively considered the coupling influence of many parameters on the optimal vacuum, including circulating cooling water temperature, cooling water flow, vacuum pump output, condenser cleanness, and makeup water. This model can not only simulate the thermodynamic parameters of the condensation-steam system on operation conditions, but also simulate the influence of the health status of condensation-steam equipments on the operating performance. The accuracy of this model is validated by comparing the simulation results with design parameters under different conditions. We studied the optimal vacuum on off-design conditions using the model. The research shows that the change of the vacuum pump output will affect the results of the optimum circulating water flow, so the net power of the unit should be calculated with consideration of the change of the vacuum pump output in order to get the more practical optimal circulating water flow. The cleanliness of heat transfer surface has a great influence on the optimum circulating water flow. When the cleanliness is poor, the unit needs larger circulating flow to maintain the optimal vacuum. We should estimate the cleanliness of heat transfer surface to arrange suitable cleaning interval time according to the operation conditions of the unit.