Diabetic patients face an increased risk of cataract development. This study investigates the molecular mechanism by which oxidative stress activates the NLRP3/caspase-1/gasdermin-D (GSDMD) pathway, leading to inducing pyroptosis in human lens epithelial cells (HLECs) exposed to high glucose (HG) environments. In vitro, HLECs were cultured in HG medium and treated with N-acetylcysteine (NAC), MCC950 (an NLRP3 inflammasome inhibitor), and VX-765 (a caspase-1 inhibitor). Cell viability was assessed using CCK-8. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), lactate dehydrogenase (LDH) levels and activities of superoxide dismutase (SOD) and catalase (CAT) were measured using biochemical kits. Active interleukin (IL)-18 and IL-1β levels in cell culture supernatants were quantified using ELISA kits. Western blot analysis determined levels of GSDMD, GSDMD-N, NLRP3, apoptosis-associated speck-like protein containing CARD (ASC) and cleaved caspase-1. HG induced oxidative stress in HLECs, as indicated by elevated cellular ROS and MDA levels, decreased GSH level, and reduced SOD and CAT activities. HG triggered HLEC pyroptosis, characterized by increased LDH release, levels of cell pyroptosis-related proteins GSDMD-N/gSdMd ratio, and active IL-1β and IL-18 in cell culture supernatants. Inhibition of oxidative stress by NAC partially reversed HG-induced pyroptosis in HLECs. HG induced oxidative stress, activating the NLRP3 inflammasome activation and cleaving caspase-1 cleavage in HLECs. MCC950-suppressed NLRP3 inflammasome activation or VX765-inhibited caspase-1 cleavage partially reversed HG-induced HLEC pyroptosis. Oxidative stress in HLECs under HG conditions induces pyroptosis via the NLRP3/caspase-1/GSDMD pathway.