Cancer incidence and mortality rate are growing worldwide. The effectiveness of cancer therapy depends on the degree of cancer development. Anticancer prevention, screening tests, detection of precancerous conditions or cancers at an early stage of development help to prevent the development of cancer, and in the event of cancer development, they provide the best chance for a full recovery. However, in most cases of advanced cancer, there is no method that can fully cure this disease. Recently, natural products have gained more attention in cancer therapy. Panax ginseng (PG), one of the most popular natural products, is reported to have a wide range of pharmacological activities in cancer. Therefore, the anti-cancer effects and mechanisms of PG and its metabolites (compound K, Ginsenoside Rh1, Rh2, Rh3 and F1) in five major cancers (lung cancer, breast cancer, colon cancer, prostate cancer and stomach cancer) are reviewed in this study. It is confirmed that PG and its metabolites regulated apoptosis, epithelial mesenchymal transition (EMT), angiogenesis, cell cycle arrest and multidrug resistance (MDR) in vitro and in vivo cancer models. In particular, ginsenoside Rh2 showed anticancer effects in all five major cancers. This review could improve the understanding of anticancer mechanisms of PG and its metabolites against major five cancers. Further clinical studies are needed for development anti-cancer drugs using PG and its metabolites.