This study investigated the inhibitory effects of 2'-benzoyloxycinnamaldehyde (BCA) on cancer cells, including various drug-resistant cancer cell lines. To observe this activity, the anticancer drug-resistant cell lines were established by continuously exposing the parental cells to 5-fluorouracil (5-FU) and cyclophosphamide (CDDP), and examining the cells with the MTT assay and flow cytometric analysis. The BCA treatment produced similar growth inhibitory effects and apoptotic cell death on the drug-resistant cancer cells as their parental cells. The activation of the p38-mitogen activated protein kinase, an increased level of reactive oxygen species (ROS) generation and downregulation of Bcl-2 were observed in both the drug resistant and non-drug resistant cell lines. The GSH treatment effectively inhibited BCA-induced apoptosis by blocking ROS generation, suggesting that ROS is a major regulator in BCA-induced apoptotic cell death. These results suggest that BCA can be a useful drug candidate for treating drug-resistant cells.