Objective To investigate the effect of Schisandra chinensis polysaccharide (SCP) on mitochondrial autophagy in skeletal muscle in exercise-fatigue mice based on the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element ARE pathway. Methods A fatigue mouse model was established by swimming training. Mice were assigned randomly to fatigue, SCP (20 mg/kg), Rhodiola rosea (8 mL/kg), inhibitor (30 mg/kg ML385), and SCP+inhibitor groups, with normal mice as the control group. Serum was separated and levels of lactic acid (LA), lactate dehydrogenase (LDH), blood urea nitrogen (BUN), and creatine kinase (CK) were detected. Liver tissue was also isolated and levels of malondialdehyde (MDA), hepatic glycogen (HG), and superoxide dismutase (SOD) were detected. Skeletal muscle tissues were isolated and muscle glycogen (MG), changes in skeletal muscle tissue in exercise fatigue, and mitochondrial morphology were detected. Gene expression levels of mitochondrial transcription factor A (TFAM) and nuclear respiratory factor-1 (NRF-1), and Nrf2, quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and LC3 protein expression levels were analyzed. Results HG, MG, SOD, TFAM mRNA, NRF-1 mRNA, Nrf2, NQO1, HO-1, and LC3Ⅱ/LC3Ⅰ were lower in the fatigue group than in the control group, while levels of LA, BUN, LDH, CK, and MDA were higher than in the control group (P<0.05). HG, MG, SOD, TFAM mRNA, NRF-1 mRNA, Nrf2, NQO1, HO-1, and LC3Ⅱ/LC3Ⅰ levels were higher in the SCP and Rhodiola rosea groups than in the fatigue group, while LA, BUN, LDH, CK, and MDA levels were lower than in the 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 in exercise-fatigue mice by activating the Nrf2/ARE pathway, effectively exerting anti-fatigue effects.