The core technique of flood forecast and pre-warning of a river basin is the numerical simulation of flood process in a complicated flood control system. According to the structural features, flood features, and flood process mechanism of a large and complicated flood control system, a 1D and 2D coupled numerical simulation model was established. The 1D model was used for the trunk river and main branches, and the 2D model was used for flood districts. The coupled 1D and 2D was used to simulate the flood regulation and process in rivers, lakes, flood districts, and floodways. A case study was conducted in the section from the Wangjiaba to Bengbu floodgates in the middle reach of the Huaihe River. The coupled model was employed to synchronously simulate the branch rivers and trunk flood of the river basin and to improve the accuracy of flood simulation, flood forecast, and regulation of the river basin. The parameters of the model for simulating the flood process of the Huaihe River Basin in 2003 were calculated and verified, and the flood process in 2007 was demonstrated. The simulated results show that the flood regulation and process can be accurately simulated by the proposed numerical model, and the accuracy requirements can be satisfied. Finally, the model was applied to the effect analysis of a four-grade emergency flood control plan in the Huaihe River Basin.