Based on the fact that 25-OCH<sub>3</sub>-PPD, a natural ginsengenin isolated from the leaves of <i>Panax ginseng</i>, is a promising lead compound, novel 25-OCH<sub>3</sub>-PPD derivatives were synthesized to find more potent anti-tumor agents by a simple and facile synthetic method. These derivatives were classified into three types and screened for their cytotoxic activities against seven human cancer cell lines. Compared with 25-OCH<sub>3</sub>-PPD, compounds <b>a5</b>, <b>a7</b>, <b>b5</b> and <b>b7</b> exhibited higher anti-tumor activities on all tested cell lines with almost 5-fold to 15-fold increases. In particular, compound <b>a7</b> showed the greatest cytotoxic activity against α-2 cells (IC<sub>50</sub> = 2.4 ± 0.4 μM). The preliminary study on the mechanisms indicated that compound <b>a7</b> could induce α-2 cell apoptosis. Structure-activity relationships demonstrated that the carbon-carbon double bond at the C-20 position could enhance the antiproliferative activity. In conclusion, the novel derivatives <b>a5</b>, <b>a7</b>, <b>b5</b> and <b>b7</b> could be further studied as potential candidates for the treatment of cancer. This research provides a theoretical reference for the exploration of new antiproliferative agents.