Aerodynamic drag reduction is a key element for the design of aircrafts, and it is also considered to be affected by the flow velocity. Herein, the influence of high flow velocity on the drag reduction induced by the surface microstructure inspired by a cross-section of barchan dune was investigated by the computational fluid dynamics method in this work. Overall, the drag reduction ratio was decreased while the pressure drag and viscous resistance enhanced simultaneously with the augmentation of flow velocity. Otherwise, drag analysis revealed that the total drag was a power function of flow velocity, which meant that the effect of flow velocity on drag was extremely fierce. Additionally, the microstructure improved the thickness of the boundary layer with a growth rate of 14.2%, and then reduced the viscosity resistance with limits during the development process of flow velocity. Furthermore, the micro-vortex caused by the surface microstructure provided the reverse wall shear stress, with the maximum value ranging from −4.77 Pa to −51.27 Pa, and then reduced the velocity gradient above the microstructure, thereby improving the drag reduction. However, both Reynolds-averaged Navier-Stokes (RANS) and large eddy simulation (LES) calculations showed that the excessive velocity could lead to the dissipation of micro-vortex, which augmented the contact area between the fluid and the surface, resulting in the enlargement of viscous resistance. Finally, it was confirmed that the variation of surface microstructure height had a significant influence on drag reduction at high flow velocity. The underlying mechanism of drag reduction could also provide theoretical guidance for the design and optimization of drag reduction coatings in aeronautical applications.