Resveratrol is a promising chemical agent that treats multiple aging-related diseases and improves life span. While reactive oxygen species undoubtedly play ubiquitous roles in the aging process and resveratrol has been shown to be an effective antioxidant, the mechanism through which resveratrol acts against oxidative stress remains unknown. Here we show that resveratrol activates SIRT2 to deacetylate Prx1, leading to an increased H₂O₂ reduction activity and a decreased cellular H₂O₂ concentration. Knockdown of SIRT2 or Prx1 by RNA interference abrogates resveratrol’s ability to reduce the H₂O₂ level in HepG2 cells. Using purified SIRT2 and a Prx1 mutant harboring acetyllysine at position 27 (Prx1–27AcK), we show that resveratrol enhances SIRT2’s activity to deacetylate Prx1–27AcK, resulting in a significantly increased H₂O₂ reducing activity. Thus, SIRT2 and Prx1 are targets for modulating intracellular redox status in the therapeutic strategies for the treatment of aging-related disorders.