Previous studies have confirmed that adiponectin (APN) plays a protective role in myocardial ischaemia-reperfusion (IR) injury, and the aim of this study was to investigate its effect on skeletal muscle. ELISA was used to detect the levels of Creatinine Kinase (CK), LDH, SOD and MDA in the plasma of the lower limbs of mice, and the levels of IL-6, IL-1β and TNF-α in the gastrocnemius. Quantitative PCR was used to detect the expression level of miR-21. TUNEL staining was used to detect the apoptosis of the gastrocnemius. The expression levels of apoptosis proteins, autophagy marker proteins and downstream target genes of miR-21 in gastrocnemius were detected by Western Blot. The results of this study revealed that APN levels were significantly reduced in gastrocnemius of IR mice. The oxidative stress, inflammatory response, apoptosis and autophagy induced by IR were significantly ameliorated by APN injection. The above effects of APN may be achieved through miR-21/PI3K signalling pathway, as found by interfering gene expression levels with miRNA antagomir and lentiviral injection. Taken together, our study revealed that APN protects skeletal muscle from IR injury through miR-21 /PI3K/Akt signalling pathway through inhibiting inflammatory response, apoptosis and autophagy.