The ISWZs (interlayer shear weakness zones) are the critical weak infilled discontinuity controlling rock mass stability in the underground caverns, dam foundations, and slopes. Given the complex occurrence characteristics of ISWZs and the limitations in the shear strength criterion, it is not easy to assess their strength variability in the field. This study presents a method to evaluate the shear strength parameters of the ISWZs in the Baihetan Hydropower Station. First, the ISWZs are classified based on the two parameters, i.e., the infilling ratio and clay content of ISWZs. Subsequently, the shear strength model for each class of ISWZs, involving the climbing/shearing off effects, is proposed according to the physical and mechanical characteristics. Finally, the strength characteristics of three typical ISWZs in the Baihetan Hydropower Station are studied systematically using the multi-index engineering geological classification method. Based on this study, a new predictive shear strength model was proposed. The obtained results in this study suggest that the strength parameters of ISWZs determined through field tests provide a more conservative result than the shear strength model presented in this study. This result may have engineering implications for designing and constructing underground caverns with large and weak ISWZs.