Objective: Age-relate cataract (ARC) is a disease of the eyes with no effective drugs to prevent or treat patients. The aim of the present study is to determine whether histone H3, alpha A-crystallin (CRYAA), beta-galactosidase (GLB1), and p53 are involved in the pathogenesis of ARC. Methods: A total of 99 anterior lens capsules (ALCs) of patients with ARC of various nuclear grades, ultraviolet models of ALCs, and two human lens epithelial cell lines (FHL-124 and SRA01/04) were used, and the expression of histone H3, CRYAA, GLB1, and p53 were detected by immunoblotting and reverse transcription and real time-quantitative polymerase chain reaction. The association between CRYAA with histone H3, GLB1, and p53 was assessed in FHL-124 and SRA01/04 cells following CRYAA overexpression. Results: Histone H3 and p53 in ALCs of patients with ARC were up-regulated in a grade-dependent manner, and the expression of CRYAA showed a positive association with histone H3, p53, and GLB1. In UV models of ALCs and human lens epithelial cell lines, the expression levels of histone H3, cell apoptosis factors (Bax/Bcl-2, cleaved caspase-3), and inflammation factors (interleukin-6, tumor necrosis factor-alpha) were all up-regulated. Furthermore, transfection of CRYAA in FHL-124 cells induced overexpression of histone H3. Conclusion: CRYAA-mediated upregulation of histone H3 may be involved in the pathogenesis of ARC. p53 may also have a role in ARC development, but not via the CRYAA-histone H3 axis. The results of the present study may assist in improving our understanding of the pathogenesis of ARC and in identifying potential targets for treatment.