To study the additional resistance effect of the moonpool during the navigation of the drilling vessel, this paper explores the variation of the drilling vessel resistance under different waves based on a model test and numerical simulation. The difference between the model test and the numerical simulation results is compared, and the mechanism of the added resistance of the moonpool under different waves is revealed. The results show that the technology of numerical simulation is able to accurately simulate the navigation resistance of the drilling vessel in waves. The numerical simulation results closely correspond to the experiment results, and the error range can be controlled within 10%. In the components of the total resistance of the hull, pressure resistance plays a dominant role when the drilling vessel sails in waves. The pressure resistance accounts for about 60%–70% of the total resistance, while the friction resistance accounts for about 30%–40% of the total resistance. At low speed, the average resistance reduction rate of the dissipative equipment is 4.4%; under the condition of medium speed, it is 7.5%; at high speed, it is 9.6%; and the resistance reduction efficiency of the dissipative equipment increases with the increase in speed. The dissipative equipment partially suppresses the eddy's action stage and prevents eddy shedding from entering and directly hitting the back wall, thereby reducing the moonpool's additional pressure resistance. The research results can provide a reference for energy savings and emission reductions in drilling vessels.