The weak interlayer zone (WIZ) is a high-risk geotechnical system with poor mechanical properties, strong ductility, loose structure, and wide distribution. To comprehensively investigate the uncoordinated deformation characteristics and failure mechanism of rock mass with WIZ, a series of uniaxial loading tests using digital image correlation (DIC) technique, and numerical simulation tests were carried out. Besides, the damage constitutive model of rock mass with WIZ was established, then the damage evolution law was also analyzed. Results show that a high strain localized zone appears in the WIZ from the beginning of loading, which then develops towards the contact surface between the WIZ and the rock mass. As loading proceeds, the WIZ exhibits layered spalling and ultimately forms through-cracks after the initiation of micro-cracks, and vertical tensile cracks to appear in the rock. causing vertical tensile cracks to appear in the rock. With the increase of the WIZ thickness and dip angle, the uniaxial compressive strength and deformation modulus of specimen show a negative exponential decay. When rock mass with WIZ collapse, the bonding of WIZ particles fails and the number of tensile-shear cracks gradually increases, eventually resulting in the plastic squeezing-out of WIZ. Moreover, the particles of the rock masses with smaller WIZ dip angles are mainly displaced vertically, and the failure is mainly caused by tensile splitting. The significant lateral displacement of particles in the rock mass with larger WIZ dip angles leads to the destruction of the rock mass mainly through shear slip, in particular a pronounced sliding down along the WIZ. Furthermore, the damage constitutive model of the rock mass with WIZ was established by distinguishing the total damage of the rock mass with WIZ into the damage of the WIZ and the damage of the rock mass. The model prediction results show that the total damage D increases with the increase of WIZ thickness and dip angle, and develops faster in the early stage and slower in the later stage. The research can provide effective basis and feasible ideas for the uncoordinated deformation and failure evolution, macro–micro failure mechanism, as well as the constitutive model of rock mass with WIZ in underground cavern under high geostress.