Diabetic cataract (DC), a well-recognized complication in diabetic patients, can progress to blindness if not adequately managed, with currently limited therapeutic strategies. Icariin (ICA), a natural compound derived from Epimedium, has been demonstrated exhibiting anti-inflammatory and anti-oxidant, but its impact on diabetic cataracts remains elusive. In this study, we used both in vitro SRA01/04 cells and in vivo SD rats' model to explored the protective effects of ICA in cataract formation. Following network pharmacology, proteomic and surface plasmon resonance (SPR) analyses further demonstrated that ICA interacts with insulin-like growth factor-binding protein-3 (IGFBP3) and modulates oxidative stress as well as apoptosis via the PI3K/AKT signaling pathway. These findings collectively demonstrated that ICA could alleviate high glucose-induced oxidative stress and cell apoptosis in vitro and in vivo, suggesting that ICA is a potent natural compound with protective effects in DC, offering an effective therapeutic approach for the disease management.