AIM: To investigate the therapeutic effect of crocetin on diabetic lower limb ischemia and explore its underlying mechanism. METHODS: Male C57BL/6J mice aged 8 weeks were used to establish a diabetic mouse model through intraperitoneal injection of streptozotocin (STZ). Following successful induction of diabetes, femoral artery ligation (FAL) surgery was performed to create a model of diabetic lower limb ischemia. Fourteen days after STZ injection, the mice were treated with crocetin (3 mg/kg and 6 mg/kg) by gavage for 21 consecutive days. Post-FAL surgery, Doppler flowmetry was employed to assess blood flow in the mice of each group. Immunofluorescence staining techniques were utilized to observe the expression levels of platelet-endothelial cell adhesion molecule (CD31), α-smooth muscle actin (α-SMA), and inflammatory-related factors including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and transforming growth factor-β (TGF-β) in the gastrocnemius muscle of diabetic mice with lower limb ischemia. RESULTS: Compared to the normal group, the model group exhibited significantly elevated blood glucose levels and significantly reduced lower limb blood flow (P<0.05). While CD31 and α-SMA expression showed no significant change, the expression levels of TNF-α, IL-1β, IL-6, and TGF-β were significantly increased (P<0.05, P<0.01, P<0.05, P<0.05). Compared to the model group, crocetin-treated groups showed no significant change in blood glucose levels but demonstrated significantly increased lower limb blood flow (P<0.05). The high-dose crocetin group (6 mg/kg) significantly enhanced CD31 and α-SMA expression (P<0.0001, P<0.05) and significantly reduced the expression levels of IL-1β, IL-6, and TGF-β (P<0.001, P<0.05, P<0.05). CONCLUSION: Crocetin may exert its beneficial effects on diabetic lower limb ischemia through anti-inflammatory and angiogenic mechanisms.