Objective To study the cardioprotective effect of sesame ethanol extract （SEE） on exercise-induced fatigue （EIF） rats and its effects on myocardial physiological and biochemical parameters.Methods Rats were randomly divided into control group （Control）， EIF group， EIF+0.5SEE group， EIF+1SEE group and EIF+2SEE group， with 12 rats in each group. The rats in control group and EIF group were daily intragastrically administered 2 mL of purified water for 14 consecutive days. Rats in EIF+0.5SEE group， EIF+1SEE group and EIF+2SEE group were given 0.5， 1.0 and 2.0 g/kg·BW of SEE daily for 14 consecutive days. Then the EIF rat model was established by treadmill exercise. After exercise， the echocardiographic parameters （LVPWd， LVPWs， LVIDs， EF and FS）， serum myocardial injury indexes （LDH， CK and cTnI） and myocardial tissue antioxidant indexes （MDA， SOD， CAT and GSH-Px） of the rats in each group were detected. Myocardial morphology was detected by hematoxylin and eosin （HE） staining. The protein expressions of connexin 43 （Cx43）， ATP 5D， phosphorylated AMP-dependent protein kinase （p-AMPK） and AMPK in myocardial tissue were detected by Western blot.Results Compared with EIF group， the LVPWd， LVPWs and LVIDs of EIF+0.5SEE group， EIF+1SEE group and EIF+2SEE group decreased， while EF and FS increased significantly （P<0.05）. Compared with EIF group， the myocardial injury in EIF+0.5SEE group， EIF+1SEE group and EIF+2SEE group was significantly alleviated， and the levels of serum LDH， CK and cTnI decreased significantly （P<0.05）. Compared with EIF group， the myocardial tissue MDA content in EIF+0.5SEE group， EIF+1SEE group and EIF+2SEE group decreased significantly， while the activities of SOD， CAT and GSH-Px increased significantly （P<0.05）. Compared with EIF group， the expression levels of Cx43， ATP 5D and p-AMPK/AMPK protein in myocardial tissue of EIF+0.5SEE group， EIF+1SEE group and EIF+2SEE group all increased significantly （P<0.05）.Conclusion SEE can effectively prevent myocardial injury and improve cardiac function in EIF rats. SEE may exert cardioprotective effects by improving antioxidant system， gap junctions， energy metabolism and mitochondrial biogenesis in myocardial tissue.