Objective To investigate the protective effect of sodium aescinate on skeletal muscle ischemia-reperfusion injury in rats. Methods Thirty rats were divided into three groups: normal group (blank group), ischemia-reperfusion group (control group), and sodium aescinate-treated ischemia-reperfusion group (experimental group), 10 cases in each group. Skeletal muscle was obtained for hematoxylin-eosin (HE) staining; biochemical analysis determining expression of myoglobin (MB), lipoprotein complex (LPC), and lipid peroxide (LPO); real-time fluorescent polymerase chain reaction (qPCR) detecting expression of inducible nitric oxide cyclase (iNOS) and antioxidant enzymes (GPX1, CAT, and SOD2); enzyme-linked immunosorbent assay (ELISA) detecting expression of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumors Necrosis factor-α (TNF-α). Results HE staining: myofibrillar disorders and edema in the control group compared with the blank group; less inflammatory cell infiltration in the experimental group. Biochemical analysis: compared with the blank group, MB, LPC and LPO [2.22±0.22, 3.52±0.18, 2.38±0.14 (nmol/mg)] increased in the control group, and 1.16±0.22, 1.57±0.19, 1.33±0.26 (nmol/mg)] decreased in the experimental group compared with the control group. The above differences are statistically significant (P＜0.05). Conclusion Sodium aescinate can reduce the expression of inflammatory factor-muscle necrosis products, reduce oxidative stress, and protect skeletal muscle ischemia-reperfusion injury.