To investigate the influence of mesoscopic heterogeneity and confining pressure on the mechanical properties of granite under cyclic loading, a series of biaxial compression tests were conducted on granite samples with different mineral crystal size distributions using Particle Flow Code (PFC) software. A grain-based model was established to explore the effects of crystal size distribution-induced mesoscopic heterogeneity, confining pressure, and cyclic loading on rock mechanics parameters. The mesoscopic damage mechanism was analyzed from a microscopic perspective. The results showed that confining pressure and heterogeneity significantly affected the mechanical behavior and damage mechanisms of rock samples under both compressive and cyclic loading. As confining pressure increased, the peak strength, elastic modulus, and strain of the rock gradually increased, but the growth rate slowed down, mainly due to the micro-crack closure and compaction effects induced by the confining pressure. The increase in heterogeneity led to a gradual decrease in the peak stress and elastic modulus of the rock, and the influence of heterogeneity on these mechanical parameters weakened as confining pressure increased. The number of micro-cracks in the rock passed through three stages: slow growth, lag growth, and accelerated growth. Under high confining pressure, the failure mode of the rock tended to be ductile, accompanied by plastic deformation and crack closure, while heterogeneity accelerated crack propagation. The mechanical properties of granite were significantly affected by its mineral composition and hardness differences. The existence of a hardness gradient intensified local crack propagation and affected the overall mechanical behavior and damage evolution of granite.