Chemotherapy induces Myeloid-Derived Suppressor Cells (MDSCs) to be the primary negative regulator of immunity in the Tumor Microenvironment (TME). MDSCs inhibit cellular immune responses by enhancing tumor immune escape, severely endangering human survival and health. Agents selectively targeting MDSCs are currently in paucity. This study developed a novel traditional Chinese medicine formula Yisui Shengxue (YSSX) Capsule to mitigate post-chemotherapy immunosuppression. A clinical trial validated that this formula could improve White Blood Cell (WBC), Neutrophil (NEUT), and lymphocyte (LYM) counts in the peripheral blood of patients. Network pharmacology analysis showed that active ingredients of YSSX can target arginine synthesis and immune-inflammatory pathways. In vivo experiments revealed that YSSX significantly suppressed the JAK2/STAT3 pathway in mice with CTX-induced postchemotherapy leukopenia. In addition, YSSX inhibited IL-10, Arg-1, iNOS, and ROS, and increased IFN-? release, thereby decreasing MDSCs amplification and recovering T cell function and activity. To conclude, YSSX can attenuate MDSCs-mediated arginine and NO metabolism by modulating the JAK2/STAT3 signaling pathway to mitigate post-chemotherapy immunosuppression. Thus, YSSX is a potential agent for post-chemotherapy immunosuppression.