Background: Zingiber zerumbet locally known as lempoyang is used traditionally to cure swelling, sores, and loss of appetite. Its rhizomes contain many active compounds such as zerumbone and kaempferol that have been shown to exhibit antiproliferative activities on various cancer cell types. However, the effect of this plant on leukemia has not thoroughly been investigated. Objective: This study was conducted to investigate the cytotoxic effects of Z. zerumbet ethyl acetate crude extract on apoptosis-resistant erythroleukemia cell line, K-562. Materials and Methods: The cytotoxic effects and morphological changes of Z. zerumbet ethyl acetate crude extract on apoptosis-resistant erythroleukemia cell line, K-562, were investigated spectrometrically through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and morphologically using the phase-contrast microscopy, respectively. Results: MTT assay demonstrated that this crude extract showed cytotoxic effects on erythroleukemia cell line K-562 in a dose-dependent and time-dependent manner with IC50values of 13.83 ± 1.82 and 10.13 ± 1.67 μg/ml for 48 and 72 h time points, respectively. The morphology of treated cells showed apparent changes of features such as membrane blebbing, cell shrinkage, and formation of apoptotic bodies which were the signs of apoptosis. The changes of cell morphology that resembled apoptotic features were more obvious with increase in treatment time. Conclusions: This finding indicates that ethyl acetate crude extract of Z. zerumbet exhibits cytotoxic effects on K-562 cell line through induction of apoptosis as morphologically seen in the cells. Further investigations are needed to ascertain the possibility of apoptosis as its major event of cell death.