Background: 20(R)-ginsenoside Rg3 (R-Rg3) is a kind of ginseng glycol tetracyclic triterpenoid saponin, which is a recognized traditional Chinese medicine monomer and has the action of inhibiting the proliferation of tumor cells. Objectives: The goal of our experiment was to investigate the protective function of R-Rg3 on chemotherapy-induced myelosuppression in mice. Materials and Methods: Cyclophosphamide (CTX) was injected into the intraperitoneal (i.p.) to establish the mice myelosuppression model. We measured the number of peripheral blood cells (PBCs), and the number of bone marrow nucleated cells (BMNCs) was counted. Hematopoietic progenitor cells (HPCs) were cultured in vitro, and the amount of cell colonies was recorded at different times. Then ELISA was used to detect the levels of hematopoietic-related cytokines and flow cytometry was employed to test cell cycle. The network pharmacology was used to predict the main pathways of action. Furthermore, the expression of p-JAK2 and p-STAT5 was detected via western blotting. Results: The experimental outcomes showed that R-Rg3 could improve the amount of PBCs in mice with myelosuppression, increase the quantity of karyota cells in bone marrow, and enhance the proliferation of HPCs and adjust the content of hematopoietic-related cytokines. Moreover, the JAK–STAT signaling pathway may be the key to the role of R-Rg3. Conclusion: All of these results implied that R-Rg3 might be a therapeutic agent for myelosuppression after chemotherapy.