Abstract：Objective：To observe the effect of Zhizhu Liujunzi Decoction combined with GP regimen on cancer-related fatigue (CRF) in patients with non-small cell lung cancer (NSCLC). Methods： A total of 110 NSCLC patients were divided into the control group and the treatment group， with 55 cases in each group， using a random number table method. The control group was treated with GP regimen， and the treatment group was treated with GP regimen combined with Zhizhu Liujunzi Decoction. Compared the traditional Chinese medicine (TCM) syndrome scores， tongue coating thickness scores， Cancer Fatigue Scale (CFS) scores，and levels of T lymphocytes and serum tumor factors before and after treatment in the two groups， and evaluated the clinical efficacy and incidence of adverse reactions in the two groups. Results： After treatment， the total disease control rate (DCR) was 94.55% in the treatment group， and 81.82% in the control group，and the DCR of the treatment group was higher than that of the control group (P＜0.05). After treatment， the TCM syndrome scores， tongue coating thickness scores， CFS scores， cytokeratin fragment 21-1 (CYFRA21-1)，carbohydrate antigen (CA125)，carcinoembryonic antigen (CEA)， neuron specific enolase (NSE) and CD8+ levels in both groups were lower than those before treatment (P＜ 0.05)， and the TCM syndrome score， tongue coating thickness score， CFS score， CA125， CEA， CYFRA21-1， NSE and CD8+ level in the treatment group were lower than those in the control group (P＜ 0.05). After treatment，the levels of CD3+， CD4+， and CD4+/CD8+ in both groups were higher those than before treatment (P＜0.05)， and the levels of CD3+， CD4+， and CD4+/CD8+ in the treatment group were higher than those in the control group (P＜0.05). The incidence of adverse reactions was 34.55% in the treatment group， lower than that of 54.55% in the control group (P＜0.05). Conclusion： Zhizhu Liujunzi Decoction combined with GP regimen has a definite therapeutic effect on NSCLC，which can alleviate CRF symptoms，regulate immune function，reduce serum tumor factor levels，and has high safety.