The protection project of inverted siphon in the confluence reach of Tangbai River of North Hubei Water Transfer Project is studied in this paper. A hydrodynamic model coupling 1D model of Tanghe River and Baihe River and 2D model of Jiahetao reach was established for this protection problem. In consideration of various extreme unfavorable factors, e.g., dike breaches and dike flooding, the range and degree of flooding impact under different design flood standards were calculated and analyzed. Meanwhile, the impacts of dike breaching and overbank flooding on project route were examined by physical model test under the most unfavorable condition in the presence and in the absence of protection. Numerical simulation results indicated that large flooding velocity was mainly found in the adjacent of breach, where severe scour will be induced at adjoining project route. Moreover, different protection levels and ranges were determined according to the deformation of grille-cage with gravels and the range of scour pit and erosion-resistance flow rate obtained from numerical simulation and erosion experiment. The research results offer support and basis for the design of protection scheme for the inverted siphon protection project in this study.