PURPOSE: The study aims to investigate the therapeutic effects of the aqueous extract of Atractylodes macrocephala Koidz. (AEA) on dexamethasone (Dex) -induced sarcopenia in mice and to explore its possible mechanisms of action. METHODS: This study utilized bioinformatics analysis to explore the primary pathogenic mechanisms of age-related sarcopenia and Dex-induced muscle atrophy. In animal experiments, a mouse model of muscle atrophy was established using Dex, and different doses of AEA were administered for treatment. The therapeutic effects of AEA were evaluated through tests of motor ability and histological analysis, and the molecular mechanisms predicted by bioinformatics were verified by measuring the expression levels of related genes. RESULTS: Bioinformatics analysis suggests that there may be shared pathogenic mechanisms related to mitochondrial function and structure between age-related sarcopenia and Dex-induced muscle atrophy. Dex significantly reduced the mass, function, and cross-sectional area of muscle fibers in mice, and also induced changes in muscle fiber types. In contrast, AEA significantly ameliorated the aforementioned atrophic effects caused by Dex. The modulation of mitochondrial biogenesis and dynamics may be a crucial mechanism by which AEA exerts its anti-sarcopenia effects. CONCLUSION: AEA can significantly alleviate the symptoms of Dex-induced skeletal muscle atrophy in mice by improving mitochondrial function, indicating its potential for clinical application in the prevention and treatment of age-related sarcopenia.