Abstract: Objective: To investigate the effect and mechanism of astaxanthin on retinal damage in diabetes mice. Methods: The mice were randomly divided into four groups: Normal group, model group, low-dose astaxanthin group and high-dose astaxanthin group. Retinal injury model of diabetes mice induced by intraperitoneal injection of streptozotocin (STZ) combined with high-fat diet. The fasting blood glucose and insulin resistance were measured by blood glucose meter. The levels of malondialdehyde (MDA) and Fe²⁺, the activities of glutathione peroxidase (GSH-PX) and superoxide dismutase (SOD) in mouse retina were measured by spectrophotometry. The expression levels of glutathione peroxidase 4 (GPX4), nuclear factor E2 related factor 2 (Nrf2), transferrin receptor 1 (TFR1), and ferritin heavy chain 1 (FTH1) in mouse retina were determined by immunoblotting. Observation of pathological changes in the retina of mice in each group using HE staining method. Results: The astaxanthin could reduce the level of fasting blood glucose in diabetic mice (P<0.05, P<0.01) and high dose of astaxanthin could ameliorate the insulin resistance of diabetic mice (P<0.01). Astaxanthin could reduce the contents of MDA and Fe²⁺ in the retina of diabetes mice, and increased the activities of GSH-PX and SOD (P<0.05, P<0.01). In addition, the results of western blotting showed that astaxanthin could significantly increase the expression of GPX4, Nrf2, FTH1 protein in the retina of diabetes mice, and reduced the expression of TFR1 protein (P<0.05, P<0.01). The pathological section results showed that, after the intervention of astaxanthin, the damage of mouse retinal inner nuclear layer cells, outer nuclear layer cells and mouse retinal ganglion cell layer were significantly reduced. Conclusion: Astaxanthin could inhibit iron death through antioxidation and up-regulation of Nrf2/GPX4 signaling pathway, and alleviate retinal damage in diabetes.