Human mesenchymal stem cells (hMSCs) are considered a highly promising candidate cell type for cell-based tissue engineering and regeneration because of their self-renewal and multi-lineage differentiation characteristics. Increased levels of reactive oxygen/nitrogen species (ROS/RNS) are associated with tissue injury and inflammation, impact a number of cellular processes, including cell adhesion, migration, and proliferation, and have been linked to cellular senescence in MSCs, potentially compromising their activities. Naturally occurring polyphenolic compounds (polyphenols), epigallocatechin-3-gallate (EGCG), and curcumin, block ROS/RNS and are potent inflammation-modulating agents. However, their potential protective effects against oxidative stress in hMSCs have not been examined. In this study, we carried out a systematic analysis of the effects of polyphenols on hMSCs in their response to oxidative stress in the form of treatment with H2O2 and S-nitroso-N-acetylpenicillamine (SNAP), respectively. Parameters measured included colony forming activity, apoptosis, and the levels of antioxidant enzymes and free reactive species. We found that polyphenols reversed H2O2-induced loss of colony forming activity in hMSCs. In a dose-dependent manner, polyphenols inhibited increased levels of ROS and NO, produced by H2O2 or SNAP, respectively, in MSCs. Notably, polyphenols rapidly and almost completely blocked H2O2-induced ROS in the absence of significant direct effect on H2O2 itself. Polyphenols also protected the antioxidant enzymes and reduced apoptotic cell death caused by H2O2 exposure. Taken together, these findings demonstrate that EGCG and curcumin are capable of suppressing inducible oxidative stress in hMSCs, and suggest a possible new approach to maintain MSC viability and potency for clinical application. J. Cell. Biochem. 114: 1163–1173, 2013. © 2012 Wiley Periodicals, Inc.