Cancer-related fatigue (CRF) not only has a negative impact on work, daily activities and social relationships, but also be a predictor of cancer patients' survival. And it has no FDA-approved therapy. ShenQi FuZheng Injection (SFI) is clinically used for adjuvant treatment of lung cancer and gastric cancer. And we found that SFI can improve the incidence of CRF in patients with gastric cancer. However, its efficacy against CRF remains to be elucidated. In the present study we established a tumor-bearing mouse fatigue model, conducted the forced swim test (FST) and grip strength measurements to evaluate the therapeutic effect of SFI. Additionally, we detected inflammation and immune indicators. The result showed that SFI administration could reduce depressive-like behaviors in tumor-bearing mice and inhibit tumor growth. In addition, SFI might improve fatigue symptoms by inhibiting pro-inflammatory cytokines produced by peripheral immune cells, restrain the dysfunction of exhausted T cells and improve the anti-tumor immunity through the targets of PDL1, TIM3 and FOXP3. These data suggested that SFI might be useful in alleviating CRF and provide further support to confirm SFI as a potential therapy for CRF in humans.