Abstract: Objective To determine whether a diet high in S-adenosylmethionine (SAM) promotes DNA demethylation through the activation of ten-eleven translocation protein 3 (TET3), thereby inhibiting neuronal apoptosis and reactive oxygen species (ROS) production in mice following stroke. Methods C57BL/6J mice were divided into three groups: a Sham group, a middle cerebral artery occlusion (MCAO) group, and a SAM group. After surgery, the Morris water maze test was used to assess neurological function. Mouse brain tissues were collected, sectioned, and stained with hematoxylin-eosin, triphenyltetrazolium chloride (TTC), and immunofluorescence. PC-12 cells were divided into Control, hypoxia/reoxygenation (H/R), and SAM groups. ROS levels and apoptosis were measured using flow cytometry. The expression of TET3 was detected by Western blot, and the level of 5-hydroxymethylcytosine (5hmC) was analyzed by Dot blot. Results In animal experiments, compared with the Sham group, the MCAO group exhibited worsened neurological deficits, significant brain infarction areas, disorganized brain tissue structure with numerous vacuoles, reduced neuronal cell count, decreased TET3 protein expression in brain sections, and reduced 5hmC levels. In contrast, the SAM group showed less neurological deficits, smaller brain infarction areas, fewer vacuoles, more surviving neurons, higher TET3 protein expression, and higher 5hmC levels than the MCAO group. In cell experiments, compared with the Control group, the H/R group exhibited increased ROS production, induced cellular apoptosis, reduced intracellular TET3 protein expression, and decreased 5hmC levels. However, compared with the H/R group, the SAM group showed reduced ROS production, decreased apoptosis, increased TET3 expression, and elevated 5hmC levels. The effect of SAM in reducing apoptosis was abolished by the administration of a TET3 inhibitor. Conclusions A diet high in SAM exerts protective effect by reducing neuronal damage after stroke in mice through TET3-mediated demethylation.