To improve the computing efficiency of the computational fluid dynamics (CFD) simulation of reactor pressure vessel (RPV), a novel CFD simulation scheme for RPV was proposed by combining the multiple RANS model (MRANS) with CFD simulation. The accuracy of the CFD simulation scheme using MRANS for RPV was guaranteed by optimizing the domain division technology and the data transmission method of traditional MRANS scheme which is used in rod bundle simulation. First, a CFD simulation of the integrated RPV model was carried out, and the validity of the CFD method was verified by comparing the calculated results with the experimental data. Then, based on the domain overlapping approach, the domain division model of downcomer (DC) and lowerplenum (LP) was built, and the modeling of multi-domain CFD simulation was carried out by using the two-way pressure-velocity data transfer method. Next, the performance of different turbulent models in each domain was compared and analyzed aiming to select the appropriate turbulent model. Finally, taking the computing efficiency of CFD simulation as the optimization objective, two MRANS schemes (RSM-SKE and RSM-RKE) were proposed. Results show that compared with the traditional domain division simulation scheme, the velocity and pressure calculated by the two-way domain division simulation scheme based on overlapping had better consistency with the integrated simulation results. The computing efficiency of the optimized MRANS scheme increased by 28.75% compared with the traditional single RANS model scheme, which proved that the optimized MRANS scheme has high efficiency in CFD simulation of RPV. The research results provide a new way of improving the efficiency of CFD simulation for RPV.