Malignant rhabdoid tumor (MRT) is a rare aggressive pediatric cancer characterized by inactivation of SNF5, a core subunit of SWI/SNF complexes. Previously, we showed that SNF5 contributes to transcriptional activation of NOXA, a pro‐apoptotic protein that binds and inhibits the anti‐apoptotic protein MCL‐1. In this study, we found that NOXA expression was downregulated in MRT cell lines as well as in clinical MRT samples and that ectopically expressed NOXA bound MCL‐1 and increased the sensitivity of MRT cell lines to doxorubicin (DOX) by promoting apoptosis. Consistent with this finding, knockdown of MCL‐1 in MRT cell lines induced apoptosis and increased DOX sensitivity in MRT cells, and the MCL‐1 inhibitor TW‐37 synergized with DOX to induce MRT cell death. Our results suggest that modulation of the NOXA/MCL‐1 pathway may be a potential strategy for the treatment of patients with MRT. J. Cell. Physiol. 231: 1932–1940, 2016. © 2015 Wiley Periodicals, Inc. We show that NOXA expression is downregulated in malignant rhabdoid tumor (MRT) and that ectopic NOXA expression or knockdown of MCL‐1 induces apoptosis and increases DOX sensitivity in MRT cells. Moreover, the MCL‐1 inhibitor TW‐37 synergizes with DOX to induce MRT cell death. Our results suggest that modulation of the NOXA/MCL‐1 pathway may be a potential strategy for treatment of patients with MRT.