The trophoblast cells which form the placenta, have a high potential for invading other tissues. Owing to certain mechanisms, trophoblast cells may lose their ability to control cell proliferation, and develop into pregnancy-related tumors, known as choriocarcinomas. Choriocarcinomas mostly develop from the hydatidiform mole, which is frequently found in pregnant women. Owing to their ability to rapidly metastasize through the hematogenous route, choriocarcinomas are very hard to cure if not detected at the proper time. Although numerous studies are attempting to identify the major pathways in choriocarcinoma cells, the critical pathway responsible for the origin of choriocarcinomas is still unclear. In this study, we identified that chrysin has inhibitory effects on human choriocarcinoma cells. The study demonstrated that chrysin disrupts intracellular homeostasis by altering the mitochondrial membrane potential (MMP), cytosolic Ca2+ levels, production of reactive oxygen species (ROS), and lipid peroxidation, leading to the death of choriocarcinoma cells (JAR and JEG3). Additionally, the effects of chrysin on choriocarcinoma cells were found to be mediated via the regulation of the AKT, ERK1/2, and JNK signaling pathways. Altogether, the anti-cancer effects of chrysin can aid the development of a novel therapeutic strategy against the progression of human choriocarcinomas. (C) 2018 Elsevier Inc. All rights reserved.