Abstract: Objective: This study aimed to investigate the therapeutic potential of Oligomeric Proanthocyanidins (OPC) from grape seeds against diabetic cataract (DC) and to elucidate its underlying molecular mechanism, focusing on the regulation of the miR-155-mediated glycolytic pathway. Methods: DC mouse model was established by feeding high-fat diet for 4 weeks followed by intraperitoneal injection of streptozotocin. DC model mice were randomly divided into three groups: the model group, the OPC intervention group, and the positive control proanthocyanidins (PAC) group, with a normal group serving as control. The intervention lasted for 24 weeks. Body weight, water intake, fasting blood glucose and lens opacity were monitored, hematoxylin-eosin (HE) staining was used for histopathological examination, Lactate levels in plasma and lens were measured by colorimetric assay. The mRNA expression levels of hexokinase 2 (HK2), suppressor of cytokine signaling 1 (SOCS1), hypoxia-inducible factor-1α (HIF-1α) and miR-155 in the lens were detected using quantitative real-time polymerase chain reaction (qRT-PCR). Network pharmacology and molecular docking were employed to predict the potential targets of OPC, while the protein expression level of HIF-1α was validated by immunofluorescence staining and Western Blot analysis. The intervention effects of OPC were compared with those of PAC. Results: Compared with the model group, OPC intervention increased body weight and decreased water intake from the 12th week onward (P<0.05), and reduced FBG levels (P<0.05). Lens opacities were significantly reduced by OPC from the 8th week onward (P<0.05), OPC significantly reduced the Lactic acid content in both plasma and lens tissue. Histopathological analysis revealed that OPC markedly alleviated swelling of lens epithelial cells, restored their regular arrangement, significantly reduced vacuolation, and maintained the integrity and orderly structure of the lens fiber layer. OPC significantly downregulated the mRNA expression of HK2, HIF-1α and miR-155 (P<0.01), and upregulated the mRNA expression of SOCS1 (P<0.01). Network pharmacology predicted that HIF-1α was the core target, and molecular docking showed that five main components of OPC had a strong affinity with HIF-1α, and experiment verified that OPC significantly suppressed the protein expression of HIF-1α. Although PAC intervention also demonstrated beneficial effects on these parameters, OPC was more effective than PAC in improving lens opacity, upregulating SOCS1 expression, and downregulating HIF-1α expression. Conclusion: This study provided the first evidence that OPC delays the progression of DC by modulating the HIF-1α/miR-155/SOCS1/HK2 pathway, thereby inhibiting lens glycolysis and lactate production. Moreover, OPC exhibits superior efficacy and a potentially faster onset of action compared to PAC.