Objective To investigate the effect of schisandra chinensis polysaccharide (SCP) on mitochondrial autophagy in skeletal muscle of exercise fatigue mice based on the Nrf2/ARE pathway. Methods A fatigue mouse model was established through swimming training and randomly assigned into a fatigue group, SCP (20 mg/kg) group, Rhodiola (8 mL/kg) group, inhibitor (30 mg/kg ML385) group, SCP+inhibitor group, with normal mice as the control group. Serum was separated and the levels of lactic acid (LA), lactate dehydrogenase (LDH), blood urea nitrogen (BUN) and creatine kinase (CK) were detected.. The liver was isolated, and the levels of malondialdehyde (MDA), hepatic glycogen (HG), and superoxide dismutase (SOD) were detected. Skeletal muscles were isolated, and muscle glycogen (MG), changes of skeletal muscle tissue in exercise fatigue and mitochondrial morphology were detected. The mitochondrial transcription factor A (TFAM), nuclear respiratory factor-1 (NRF-1) mRNA, Nrf2, quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and LC3protein expression were analyzed. Results The levels of HG, MG, SOD, TFAM mRNA, NRF-1 mRNA, Nrf2, NQO1, HO-1, LC3Ⅱ/LC3Ⅰ in fatigue group were lower than those in control group, while the levels of LA, BUN, LDH, CK and MDA were higher than those in control group (P<0.05). The levels of HG, MG, SOD, TFAM mRNA, NRF-1 mRNA, Nrf2, NQO1, HO-1, LC3Ⅱ/LC3Ⅰ in SCP group and Rhodiola Rosea group were higher than those in fatigue group, while the levels of LA, BUN, LDH, CK and MDA were lower than those in fatigue group (P<0.05), The above indexes were opposite in the inhibitor group (P<0.05).. Conclusions SCP promotes mitochondrial autophagy in skeletal muscle of exercise fatigue mice by activating the Nrf2/ARE pathway, effectively exerting anti fatigue effects.