Estimating the sailing resistance of unmanned submersible vehicle when navigating in the water is an important part for designing the hull profile. As there is no wave resistance when the unmanned submersible vehicle navigating in the water, so the main hull resistance mainly includes friction resistance and viscous pressure resistance. There are a lot factors affecting the resistance of the hull, including the length of bow, the length of stern, the length of middle body, the molded breadth, the molded depth, the design speed and the aspect ratio of rudder. The above factors have been selected as design variables of the resistance optimization system and the regression relationship between design variables and the frictional resistance viscous pressure resistance has been established by the response surface method, which can obtain the approximate function formula between the objective function, constraints and the design variables, providing a basis for the establishing of resistance optimization system. The design can be expanded to an overall situation by this method, then this complex disciplinary analysis can be separated from the optimization process, which can reduce the amount of calculation and optimization time. The application of polynomial response surface method in resistance optimization system has been studied in this paper and the accuracy of five polynomial response surface functions also have been studied, which reflected that the accuracy of second-order response surface is better than that of the first-order and third-order response surface. The response surface of wet area of the hull have a high fitting accuracy.