Heat shock proteins (HSPs) and histone deacetylase 6 (HDAC6) are induced under oxidative stress, which promotes oncogenesis. HSPs are regulated by heat shock factor1 (HSF1). HDAC6, a class IIb deacetylase, plays an essential role in tumorigenesis and cell stress response. HSPs, HSF1 and HDAC6 are up-regulated in cancer. In the present study, we explored the effect of curcumin, a phytochemical, on HSPs (27, 70, 90), HSF1 and HDAC6 in two different leukemia cell lines (K-562 and HL-60). The association between HDAC6, HSPs, and intrinsic oxidative stress was also investigated. Overexpression of HSPs (27, 70, 90), HSF1, and HDAC6 in leukemia cells were down-regulated by curcumin, and the effects on HSPs 27and 70 were less than that on HSP 90. This resulted in cell cycle arrest at the G2/M stage, leading to apoptosis. Different cell cycle regulatory proteins (p53, p21, cyclin B1, CDK1, Cdc25C) and some apoptosis-related proteins (Bcl-2, Bax, Bid, Bad, Apaf1, AIF and Cyt c) were altered by curcumin. Increased ROS levels in leukemia cells were quenched by curcumin. A probable association between high ROS level and the overexpression of the tumor markers was established in this study. Thus, curcumin enhanced the efficacy of anti-tumor drugs imatinib-mesylate and cytarabine through the inhibition of the tumor markers.