Background: Ginsenoside Rp1 (G-Rp1) is a novel ginsenoside derived from ginsenoside Rk1. This compound was reported to have anticancer, anti-platelet, and anti-inflammatory activities. In this study, we examined the molecular target of the antiproliferative and proapoptotic activities of G-Rp1. Methods: To examine the effects of G-Rp1, cell proliferation assays, propidium iodine staining, proteomic analysis by two-dimensional gel electrophoresis, immunoblotting analysis, and a knockdown strategy were used. Results: G-Rp1 dose-dependently suppressed the proliferation of colorectal cancer LoVo cells and increased their apoptosis. G-Rp1 markedly upregulated the protein level of apolipoprotein (Apo)-A1 in LoVo, SNU-407, DLD-1, SNU-638, AGS, KPL-4, and SK-BR-3 cells. The knockdown of Apo-A1 by its small-interfering RNA increased the levels of cleaved poly(ADP-ribose) polymerase and p53 and diminished the proliferation of LoVo cells. Conclusion: These results suggest that G-Rp1 may act as an anticancer agent by strongly inhibiting cell proliferation and enhancing apoptosis through upregulation of Apo-A1.