Endometrial　cancer　(EC)　associated　with　endogenous　hormone　metabolism,　obesity,　diabetes,　and　inappropriate　dietary　habits　has　shown　a　rising　trend　in　recent　years.　Various　therapeutics　methods　including　dietary　approaches　(vital　phytochemicals)　offer　healthy　and　nontoxic　strategies　against　cancer.　To　date,　6-shogaol　as　one　of　the　antitumor　phytochemicals　remains　unexplored　against　human　endometrial　cancer　cells.　In　our　study,　6-shogaol　obtained　from　Zingiber　officinale　rhizomes　separated　and　purified　by　HPLC,　LC-MS/MS,　and　NMR　respectively　could　inhibit　Ishikawa　cell　proliferation　at　IC50,　(24.91　mu　M)　with　the　arrested　cell　cycle　in　the　G2/M　phase.　Moreover,　it　promoted　apoptosis,　as　a　result,　triggered　ROS　production,　then　activated　key　ER　response　biomarkers　in　Ishikawa　cell　associated　with　mitochondria,　and　ultimately　regulated　related　genes　and　proteins　in　vitro　and　in　vivo.　Therefore,　6-shogaol　can　be　used　as　a　promising　natural　compound　endowed　with　potential　benefits　for　cancer　treatment　and/or　prevention　at　large　and　EC　in　particular.