Abstract: High-entropy alloys are expected to be used in aerospace, deep-sea exploration and other fields in the future, and will inevitably be affected by extreme shock loading, even will occur spall fracture. In this work, the molecular dynamics (MD) method is used to study the orientation and shock velocity dependence of the shock wave response, spall strength and microstructure evolution of single-crystal CoCrFeMnNi high-entropy alloys. The simulation results show that the elastoplastic two-wave separation phenomenon occurs when the shocking along the 110 and 111 directions and shows a trend of first strengthening and then weakening with the increase of the shock velocity. However, there is no two-wave separation phenomenon when the shocking along the 100 direction. During the shocking process, a large number of disordered structures are generated and increase with the increase of the shock velocity, which makes the spall strength decreases with the increase of shock velocity. In addition, the spall strength also exhibits orientation dependence. A large number of body-centered cubic (BCC) intermediate phases are generated when the shocking along the 100 direction, which inhibits the generation of stacking faults and disordered structures, making the highest spall strength in the 100 direction; The transformation of the relationship of the content of disordered structure in the nucleation area of microvoids at the early stage of spallation, making the spall strength in the 111 direction is higher than that in the 110 direction when the shocking velocity is low (U_p≤0.9 km/s), and slightly lower than that in the 110 direction when the shocking velocity is large (U_p ≥1.2 km/s). The research results are expected to provide theoretical support and data accumulation for the application of CoCrFeMnNi high-entropy alloys under extreme shock conditions.