Objective To investigate the mechanism of action of the Astragalus-Chinese yam combination in treating cancer-related fatigue (CRF) in mice. Methods The active components and related targets of AstragalusChinese yam were obtained from the traditional Chinese medicine systems pharmacology database and analysis platform. CRF-associated targets were identified using the GeneCards database. Intersecting targets were analyzed using the DAVID database for gene ontology and kyoto encyclopedia of genes and genomes enrichment analyses. A network diagram depicting “ drug-active component-intersecting targets-disease” was constructed using Cytoscape software, and a protein-protein interaction network was created to identify the top five core target proteins based on degree values. Molecular docking simulations were performed using Autodock Vina software. Twenty-five mice were divided randomly into a blank group and a modeling group in a 1 ∶ 4 ratio. After successfully establishing the CRF model using Lewis lung cancer cells, mice in the modeling group were further divided into model, Chinese yam (0. 2g / kg), Astragalus (0. 6 g / kg), and Astragalus-Chinese yam combination groups (0. 3 + 0. 1 g / kg) (n= 5 mice per group). The treatments were administered by gavage twice daily for 14 consecutive days. Grip-strength and forcedswimming tests were conducted. The mice were then euthanized and tissues were collected. The gastrocnemius muscles were weighed and stained with hematoxylin and eosin to reveal the muscle fiber morphology. Results A total of 23 effective active components of Astragalus-Chinese yam were identified through network pharmacology analysis,with 199 intersecting drug-disease targets. These targets mainly participated in biological processes such as protein phosphorylation through cellular components ( cytoplasm, membrane, nucleus) and performed molecular functions such as protein binding. A total of 155 signaling pathways, including pathway in cancer and the phosphatidylinositol 3-kinase-protein kinase B signaling pathway, were involved in CRF. The critical targets of Astragalus-Chinese yam for CRF included serine / threonine kinase, tumor necrosis factor, epidermal growth factor receptor, B-cell lymphoma 2,and caspase 3. The active components quercetin and diosgenin interacted with the highest number of targets and demonstrated binding energies < - 5. 0 kJ/ mol with the five core targets, indicating strong ligand-receptor binding affinity. Mice in the Chinese yam and Astragalus groups exhibited increased grip strength and prolonged swimming times compared with the model group. Gastrocnemius muscle volume and mass were increased, with well-organized muscle fibers and clear boundaries, and the effects were even more pronounced in the Astragalus-Chinese yam combination group. Conclusions Astragalus-Chinese yam treats CRF via a multi-target, multi-pathway approach,enhancing muscle strength and endurance in mice, improving gastrocnemius muscle volume and mass, and alleviating muscle atrophy, thereby mitigating the associated symptoms of CRF in mice.