With the increase of demand for materials capable of withstanding extreme service environments in fields such as advanced manufacturing, aerospace, and nuclear energy, the development of materials combining high strength, hardness, and thermal stability is of great significance. Chromium monoboride (CrB) due to its unique crystal structure and excellent mechanical properties, has attracted considerable attention; however, its deformation and failure mechanism under complex stress condition are still unclear. In this work, first-principles calculations are employed and combined with electronic structure analysis, to investigate the mechanical response and microstructural evolution of CrB under uniaxial tension, pure shear, and shear coupled with normal stress. The results show significant tensile anisotropy: the tensile strength is highest along the 100 direction (69.92 GPa) and lowest along the 010 direction (44.69 GPa). The minimum pure shear strength (35.68 GPa) occurs along the (010)100 direction. Under pure shear and low normal stress, the Cr—Cr bimetallic layers undergo interlayer slip at a critical shear strain, leading to a sudden stress drop. In contrast, under high normal compressive stress coupled with shear, the interlayer spacing between Cr—Cr bimetallic layers is significantly reduced, which enhances interlayer bonding and suppresses interlayer slip. As a result, strain energy accumulates within the crystal lattice, eventually causing an abrupt structural collapse and catastrophic failure. Further analysis shows that the effect of normal stress on shear strength is non-monotonic: it increases with pressure at low stresses but softens under high pressures. The sensitivity to normal stress varies significantly with crystallographic orientation, and the anisotropy is further amplified as pressure increases. This study elucidates the instability mechanisms of CrB under multiaxial stress, providing theoretical guidance and design reference for its applications in extreme environments.