Metformin is commonly used for treating type II diabetes and has recently been reported to possess anti-proliferative properties that can be exploited for the prevention and treatment of a variety of cancers. Ginsenosides are the main effective biological components of ginseng. It has been reported that ginsenoside-Rb2 inhibit the invasiveness of endometrial cancer cells (ECC). The aim of this study was to investigate whether protopanaxadiol (PPD, a metabolite of ginsenosides) and metformin could synergistically regulate the biological behavior of ECC and analyze its possible mechanism. We here found that either metformin or PPD treatment led to a decreased viability and increased apoptosis and autophagy levels in ECC lines (Ishikawa and RL95-2 cells), and combination of PPD and metformin could enhance these effects induced by metformin or PPD in vitro. PPD and metformin significantly decreased the expression of estrogen receptor alpha (ERα) in Ishikawa and RL95-2 cells. Estrogen promoted the viability and restricted the apoptosis and autophagy of Ishikawa and RL95-2 cells, and PPD and metformin reversed these effects. In vivo trials showed that combination of PPD and metformin had the strongest activity of anti-tumor growth compared with PPD alone and metformin alone. These data suggest that PPD and metformin can be used together to play a more powerful anti-EC effect. Our study provides a scientific basis for the clinical application of PPD and metformin in the treatment of EC, especially in estrogen-dependent patients.