Cemented paste backfill (CPB) is a type of cementitious material produced with tailings, cement, and water. Typically, CPB has a high proportion of tailings (75–80 wt%), which may contain a large amount of sulfide minerals that can cause serious attacks in the CPB system. In this study, we proposed a microstructural hydration model to investigate the influence of internal sulfate attacks (ISA) on CPB. The ISA model was verified using experimental observations and was used to investigate the microstructure and strength evolution of CPB. Finally, the proposed ISA model was implemented in PFC2D to analyze the failure mode of CPB during uniaxial compressive loading. The results of the proposed ISA model agreed well with the experimental observations. Based on this model, the microstructure evolution of CPB can be classified into solid–liquid two-phase stage and solid-phase stage. Under the influence of ISA, the short-term CPB strength (≤28 days) increased at an accelerated rate whereas the long-term CPB strength (≥56 days) decreased, which could be well explained by the proposed ISA model. The PFC2D simulation results had a good agreement with those of the experiment, and the failure mode of the CPB specimen under the influence of ISA was mainly tensile.