Background: Curcumin has been shown to exert pleiotropic biological effects, including anti-tumorigenic activity. We previously showed that curcumin controls reactive oxygen species (ROS) levels through the ROS metabolic enzymes, to prevent tumor cell growth. In this study, we synthesized 39 novel curcumin derivatives and examined their anti-proliferative and anti-tumorigenic properties. Methods and Results: Thirty-nine derivatives exhibited anti-proliferative activity toward human cancer cell lines, including CML-derived K562 leukemic cells, in a manner sensitive to an antioxidant, N-acetyl-cysteine (NAC). Some compounds exhibited lower GI50 values than curcumin, some efficiently induced cell senescence, and others markedly increased ROS levels, efficiently induced cell death and suppressed tumor formation in a xenograft mouse model, without any detectable side effects. A clustering analysis of the selected compounds and their measurement variables revealed that anti-tumorigenic activity was most well-correlated with an increase in ROS levels. Pulldown assays and a molecular docking analysis showed that curcumin derivatives competed with co-enzymes to bind to the respective ROS metabolic enzymes and inhibited their enzymatic activities. Conclusions: The analysis of novel curcumin derivatives established the importance of ROS upregulation in suppression of tumorigenesis, and these compounds are potentially useful for the development of an anti-cancer drug with few side effects.