Despite extensive efforts on studying the decomposition mechanism of HMX under extreme condition, an intrinsic understanding of mechanical and chemical response processes, inducing the initial chemical reaction, is not yet achieved. In this work, the microscopic dynamic response and initial decomposition of β-HMX with (1 0 0) surface and molecular vacancy under shock condition, were explored by means of the self-consistent-charge density-functional tight-binding method (SCC-DFTB) in conjunction with multiscale shock technique (MSST). The evolutions of various bond lengths and charge transfers were analyzed to explore and understand the initial reaction mechanism of HMX. Our results discovered that the C–N bond close to major axes had less compression sensitivity and higher stretch activity. The charge was transferred mainly from the N–NO₂ group along the minor axes and H atom to C atom during the early compression process. The first reaction of HMX primarily initiated with the fission of the molecular ring at the site of the C–N bond close to major axes. Further breaking of the molecular ring enhanced intermolecular interactions and promoted the cleavage of C–H and N–NO₂ bonds. More significantly, the dynamic response behavior clearly depended on the angle between chemical bond and shock direction.