Despite MsrA has been identified in numerous organisms, and its role in the reduction in MetO has been described well (Ruan et al., 2002; Weissbach et al., 2002), little is known about how MsrA reduces ROS to confer its antioxidant capability. Previously, the antioxidation property of MsrA is considered as the natural antioxidation activity of Met residues (Davies, 2005). Recent studies by our group and other laboratories have indicated that MsrA may exert antioxidant effect through other potential pathways (Lim et al., 2011, 2013; Wu et al., 2013a; Fan et al., 2015), such as facilitating the reaction of Met with ROS via a stereospecific Met oxidase activity (Lim et al., 2011, 2013). Although Met emerges as a good substrate for the peroxidase activity of MsrA, there are many difficulties in systematic application of methionine in vivo, for its rapid metabolism and high risk of acute coronary events (Virtanen et al., 2006). Here, we used a homology modeling tool to search the better substrates for the stereospecific methyl sulfide oxidase activity of MsrA. We found that dimethyl sulfide (DMS), a main metabolite that produced by marine algae or fermentative bacteria (Scarlata & Ebeler, 1999; Avsar et al., 2004), was a good substrate for MsrA‐catalytic antioxidation. We demonstrated that the reaction between DMS and free radicals was catalyzed by an MsrA‐dependent mechanism and this enzymatic process leads to the beneficial effects of DMS on cytoprotection and longevity.