Objectives: To investigate the effects of gavage and transdermal administration on the anti-tumor activity of QJ623 (extracts of Paris polyphylla rhizome and Tinosporae Radix) on a murine H22 solid tumor transplantation model. Materials and Methods: H22 cell suspensions were diluted to a density of 4 × 105 cells/mL with sterile saline and then injected into 6-week-old mice subcutaneously (0.2 mL) into the right anterior axilla to create a murine model of liver cancer. Tumor tissues were collected after drug administration. The tumor growth-suppression rate was calculated, and the tumor tissues were stained with hematoxylin and eosin to detect necrosis. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay was performed to observe the apoptosis. The expression of p-ACK1, p-AKT, Bax, Bcl-2, and Caspase3 in the tumor tissues was detected by western blotting. Bio-chemical kits were used to detect the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine (Cre), blood urea nitrogen (BUN), and uric acid (UA) for liver and kidney function analyses. Serum levels of IL-6, TNF-α, IFN-γ, and IL-10 were determined using enzyme-linked immuno-sorbent assay. Results: Gavage and transdermal administration of QJ623 at different concentrations reduced the tumor mass and volume to different degrees; promoted tumor cell apoptosis; decreased the expression levels of the p-AKT and Bcl-2 proteins; increased the expression of the apoptotic proteins Bax and Caspase3; increased the number of Th1 (IFN-γ) cells; decreased the number of Th2 (IL-4) and Treg cells; reduced the serum AST, ALT, BUN, UA, IL-6, TNF-α, and IFN-γ levels; and increased the IL-10 levels. Conclusion: Both gavage and transdermal administration of QJ623 showed anti-tumor effects by promoting tumor cell apoptosis, decreasing the level of inflammatory factors, increasing the number of Th1 (IFN-γ) immune cells, and decreasing the numbers of Th2 (IL-4) and Treg immune cells.