Aim: We aimed to investigate the action mechanism of Zhengyuan capsule (a registered proprietary Chinese medicine) against chemotherapy-related fatigue (CRF). Methods: BALB/c-nu nude mice model with human lung adenocarcinoma A549 xenografts was constructed by injection of A549 cell suspension. The xenografted mice were randomly divided into model, cisplatin and cisplatin+Zhengyuan groups (n = 20 each). The cisplatin group was given an intraperitoneal injection of 5 mg/ kg cisplatin every 3 days for 21 days. The cisplatin+Zhengyuan group was given an intragastric administration of cisplatin and 25 mg/kg Zhengyuan capsule each day for 21 days. Normal control and model groups were administrated with equal amount of saline. Forced swimming assay, tail suspension test, open field test, hepatic glycogen assay, blood analysis, and bone marrow smear was performed. Results: The cisplatin group developed CRF after receiving chemotherapy. When compared with cisplatin group, the cisplatin+Zhengyuan group exhibited longer exhaustive swimming time (p<0.001), shorter immobility time during tail suspension test (p<0.001), a longer total movement distance and higher average moving speed during open field test (p=0.040 and 0.03, respectively), an increased hepatic glycogen level (p<0.001), higher blood cell and bone marrow nucleated cell counts (p<0.05 or 0.001), reduced TNF-α and IL-6 levels (p=0.013 and p<0.001). These results suggested that Zhengyuan capsule alleviated the CRF in the mice. Conclusion: Zhengyuan capsule decreased the post-chemotherapy serum cytokine secretion, enhanced the hepatic glycogen content, reduced bone marrow suppression, and thereby alleviated CRF in mice.