<p>Diabetic retinopathy (DR) is a common microvascular complication of type 2 diabetes (T2D), driven by hyperglycemia-induced oxidative stress, ferroptosis, and inflammatory signaling. Here, we demonstrate that chlorogenic acid (CGA) ameliorates T2D and DR by simultaneously modulating the NRF2/xCT/GPX4 antioxidant pathway and the p-STAT3/xCT/GPX4 inflammatory-ferroptosis axis. High-fat diet (HFD) combined with streptozotocin (STZ)-induced T2D mice and high-glucose (HG)-stimulated human retinal microvascular endothelial cells (HRMECs) were used to evaluate the effects of CGA in vivo and in vitro. Network pharmacology, molecular docking, Western blotting, immunofluorescence, Seahorse metabolic assays, and site-directed mutagenesis were employed to investigate the underlying molecular mechanisms. CGA treatment significantly improved systemic metabolic parameters, including fasting blood glucose, HbA1c, and insulin sensitivity, while reducing anxiety-like behavior in T2D mice. Histological analyses revealed that CGA alleviated retinal structural abnormalities and decreased lipid droplet accumulation. Mechanistically, CGA activated NRF2/xCT/GPX4 signaling to enhance antioxidant defenses and suppress ferroptosis, while inhibiting STAT3 phosphorylation, reducing pro-inflammatory cytokines, and modulating xCT/GPX4 expression. In HRMECs, NRF2 inhibition or STAT3 activation attenuated CGA’s protective effects, highlighting the critical roles of these pathways. Molecular docking and CETSA analyses further identified N485 of STAT3 as a key residue mediating CGA binding and functional regulation. These findings indicate that CGA exerts multi-modal protective effects against DR by targeting oxidative stress, ferroptosis, and inflammation. This study provides mechanistic insight into CGA as a potential therapeutic candidate for T2D-associated retinal complications and underscores the broader relevance of NRF2 and STAT3 pathways as intervention targets in diabetes-related microvascular disorders.</p>