As a geological barrier for high-level radioactive waste (HLW) disposal in China, granite is crucial for blocking nuclide migration into the biosphere. However, the high uncertainty associated with the 3D geological system, such as the stochastic discrete fracture networks in granite, significantly impedes practical safety assessments of HLW disposal. This study proposes a Monte Carlo simulation (MCS)-based simulation framework for evaluating the long-term barrier performance of nuclide migration in fractured rocks. Statistical data on fracture geometric parameters, on-site hydrogeological conditions, and relevant migration parameters are obtained from a research site in Northwestern China. The simulation models consider the migration of three key nuclides, Cs-135, Se-79, and Zr-93, in fractured granite, with mechanisms including adsorption, advection, diffusion, dispersion, and decay considered as factors. Subsequently, sixty MCS realizations are performed to conduct a sensitivity analysis using the open-source software OpenGeoSys-5 (OGS-5). The results reveal the maximum and minimum values of the nuclide breakthrough time Tt (12,000 and 3600 years, respectively) and the maximum and minimum values of the nuclide breakthrough concentration Cmax (4.26 × 10−4 mSv/a and 2.64 × 10−5 mSv/a, respectively). These significant differences underscore the significant effect of the uncertainty in the discrete fracture network model on long-term barrier performance. After the failure of the waste tank (1000 years), nuclides are estimated to reach the outlet boundary 6480 years later. The individual effective dose in the biosphere initially increases and then decreases, reaching a peak value of Cmax = 4.26 × 10−4 mSv/a around 350,000 years, which is below the critical dose of 0.01 mSv/a. These sensitivity analysis results concerning nuclide migration in discrete fractured granite can enhance the simulation and prediction accuracy for risk evaluation of HLW disposal.