The downregulation of N-Myc downstream-regulated gene 2 (NDRG2) is known to be associated with the progression and poor prognosis of several cancers. Sensitivity to anti-cancer may be associated with a good prognosis in cancer patients, and NDRG2, which is induced by p53, sensitizes the cells to chemotherapy. However, the unique function of NDRG2 as an inducer of apoptosis under chemotreatment has not been sufficiently studied. In this study, we investigated the role of NDRG2 in chemo-sensitivity, focusing on cisplatin in U937 histiocytic lymphoma, which has the loss-of-functional mutation in p53. NDRG2 promoted the sensitivity to cisplatin through the modulation of the BAK-to-Mcl-1 ratio. The degradation of Mcl-1 and increase in BAK were mediated by JNK activation and the eIF2α/p-eIF2α pathway, respectively, which depended on PKR activation in NDRG2-overexpressed U937 (U937-NDRG2) cells. NOX5 was highly expressed in U937-NDRG2 cells and contributed to ROS production after cisplatin treatment. ROS scavenging or NOX5-knockdown successfully inhibited the sensitivity of U937-NDRG2 cells to cisplatin. Taken together, these findings indicate that NDRG2 contributed to the increased sensitivity to ciplatin through the modulation of Bak-to-Mcl-1 ratio regulated by NOX5-ROS-PKR pathway; therefore, we suggest that NDRG2 may be a molecular target for improving the efficacy of drug treatment in cancer patients.