Objective To investigate the hypoglycemic, lipid-lowering, anti-inflammatory, and antioxidant effects of crocetin in high-fat diet (HFD)-induced diabetic mice, and to preliminarily explore its regulatory effects on hepatic insulin signaling pathways and protein S-nitrosylation levels.Methods An insulin resistance model was established in C57BL/6J mice by HFD feeding. Mice were administered low (5 mg/kg), medium (10 mg/kg), or high (20 mg/kg) doses of crocetin for 8 weeks, with metformin (200 mg/kg) used as a positive control. Fasting blood glucose, oral glucose tolerance, serum insulin, lipid profiles, hepatic oxidative stress, and inflammatory cytokines were measured. Western blot was used to detect phosphorylation levels of IRS1/AKT/GSK3β pathway proteins and total protein S-nitrosylation levels in liver tissues.Results The high-dose crocetin group significantly reduced fasting blood glucose, HOMA-IR index, and OGTT AUC in diabetic mice (P0.01), improved dyslipidemia, alleviated hepatic oxidative stress and inflammatory responses, restored phosphorylation of the IRS1/AKT/GSK3β signaling pathway, and decreased total hepatic protein S-nitrosylation levels (P0.01).Conclusion Crocetin significantly improves glucose and lipid metabolic disorders and insulin resistance in diabetic mice. Its mechanisms are associated with activation of the IRS1/AKT/GSK3β signaling pathway and inhibition of oxidative stress and inflammation, accompanied by reduced hepatic protein S-nitrosylation levels, suggesting that denitrosylation may be involved in its insulin-sensitizing effects.