Combination therapies with chemotherapy and traditional Chinese medicines are attracted increasing attentions for cancer treatment in China. Shengbai decoction (SBD) is a traditional Chinese compound medicine, composed of 6 traditional Chinese herbs. The aim of this study was to investigate the synergistic anti-tumor activity of SBD with cyclophosphamide (CTX) and the possibly underlying mechanisms in treating the hepatoma 22 (H₂₂) -bearing mice. The liver cancer models in C57BL/6 mice were established by injecting with mouse H₂₂ cancer cells. Results showed that combination treatment with SBD and CTX processed a significantly synergistic anti-tumor effect in H₂₂ tumor-bearing mice. Moreover, SBD could not only improve leukopenia caused by CTX, but prolong the survival time of the mice. Furthermore, SBD could upregulate the expressions of the pro-apoptotic genes, including p53, BAD, Cas3 and Bax, and suppress the expression of anti-apoptotic gene Bcl-2. These results suggested that the combination treatment with SBD and CTX had health improving function and less side effects compared with the administration of CTX alone, and SBD could be a promising adjunct agent for liver cancer chemotherapy.