The high-temperature oxidation-resistant MoSi2 coating on the Nb substrate was prepared by slurry firing. The structure, composition and phase distribution of the coating and the relationship between these features and the oxidation resistance of the coating were investigated by SEM, EDS, and XRD. The results indicate that the interface between the coating and the substrate is metallurgical bond, and a transitional layer was formed by diffusion. The composite multi-layer structures improve the oxidation resistance properties of the coating. The method of slurry firing to prepare the high temperature MoSi2 coating on Nb was feasible. The SiO2 glass layer, which was formed on the surface of the coating by the self-oxidation of MoSi2, prevents oxygen from further diffusion. After a long time exposure in high temperature oxidizing environment, the porous microstructure was formed as a result of the diffusion of silicon in the coating. Due to further interdiffusion of the element, which takes place between the coating and the substrate, a large number of cavities which run through transversely are formed. The coating was broken through the interface between the body of the coating and the transitional layer.