Progesterone, also known as P4 (pregn-4-ene-3, 20-dione), is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Despite the physiological effects, P4 is also effective for the treatment of numerous pathological states, such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus as well as cancer. Considering the hormone microenvironment of gynecological cancers, P4 should be particularly noted in ovarian cancer. The present study demonstrated that P4 protected the ovarian cancer cell line HO-8910 from cisplatin (CDDP)-induced cell cycle arrest and restored the cell migratory capability following treatment of CDDP. Mechanistically, both progesterone receptor membrane component 1 (PGRMC1) and the progesterone receptor (PGR) were decreased in the cells treated with CDDP plus P4, while the level of progesterone receptor membrane component 2 (PGRMC2) was significantly elevated. Reversely, in the HO-8910 cells treated with CDDP alone, levels of both PGRMC1 and PGR were increased while the level of PGRMC2 was decreased. In addition to the receptor expression profile, the PI3K/AKT signaling pathway was also involved in the action of P4 in the CDDP-resistant HO-8910 cells, and a chemical inhibitor for PI3K, LY294002, significantly abolished the anti-apoptotic effect of P4. Consequently, the addition of a PI3K inhibitor to CDDP-based chemotherapy may have a more beneficial application for ovarian cancer therapy.