Hydrogen peroxide (H 2 O 2 ) mediated oxidative stress leading to hepatocyte apoptosis plays a pivotal role in the pathophysiology of several chronic liver diseases. This study demonstrates that S-allyl cysteine (SAC) renders cytoprotective effects on H 2 O 2 induced oxidative damage and apoptosis in HepG2 cells. Cell viability assay showed that SAC protected HepG2 cells from H 2 O 2 induced cytotoxicity. Further, SAC treatment dose dependently inhibited H 2 O 2 induced apoptosis via decreasing the Bax/Bcl-2 ratio, restoring mitochondrial membrane potential (㵻Ψ m ), inhibiting mitochondrial cytochrome c release, and inhibiting proteolytic cleavage of caspase-3. SAC protected cells from H 2 O 2 induced oxidative damage by inhibiting reactive oxygen species accumulation and lipid peroxidation. The mechanism underlying the antiapoptotic and antioxidative role of SAC is the induction of the heme oxygenase-1 (HO-1) gene in an NF-E2-related factor-2 (Nrf-2) and Akt dependent manner. Specifically SAC was found to induce the phosphorylation of Akt and enhance the nuclear localization of Nrf-2 in cells. Our results were further confirmed by specific HO-1 gene knockdown studies which clearly demonstrated that HO-1 induction indeed played a key role in SAC mediated inhibition of apoptosis and ROS production in HepG2 cells, thus suggesting a hepatoprotective role of SAC in combating oxidative stress mediated liver diseases. Copyright © 2018 Chitra Basu and Runa Sur. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.