Atrial fibrillation (AF) is the most prevalent sustained tachyarrhythmia in patients undergoing cardiovascular diseases. Recently, oxidative stress is considered an important contributor to AF. Therefore, antioxidant therapies for AF have great potential for clinical application. Methionine, as the other sulfur-containing amino acid residue other than cysteine, are recognized as functional redox switches, which could be rescued from its reversible oxidation of methionine sulfoxide by methionine sulfoxide reductase A (MsrA). S-methyl-L-cysteine (SMLC), a natural analogue of Met which is abundantly found in garlic and cabbage, could substitute for Met oxidations and mediate MsrA to scavenge free radicals. However, whether SMLC alleviates AF is unclear. This study aims to clarify the effects of SMLC on AF and to elucidate the underlying pharmacological and molecular mechanisms. In vivo, SMLC (70, 140 or 280 mg/kg/day) was orally administered to the mice for 4 weeks with angiotensin II (Ang II) subcutaneously infusion via osmotic pumps to induce AF. Ang II significantly prompted high AF susceptibility and atrial remodeling characterized by oxidative stress, conductive dysfunction and fibrosis. SMLC played a remarkable protective role in Ang II-induced atrial remodeling, dose-dependently. Moreover, RNA sequencing was performed on atrial tissues to identify the differentially expressed mRNA, which was screen out MSRA, CAMK2 and MAPK signaling pathway. Western blots confirmed that Ang II-induced downregulation of MsrA and upregulation of oxidated CaMKII (ox-CaMKII) and p38 MAPK could be concentration-dependently reversed by SMLC. To investigate mechanisms, HL-1 cells (mouse atria-derived cardiomyocytes) treated with Ang II were used as in vitro model. SMLC alleviated Ang II-induced cytotoxicity, mitochondrial damage and oxidative stress. Additionally, knockdown MsrA could attenuate the protective effects of SMLC, which were eliminated by the p38 MAPK inhibitor SB203580. In summary, the present study demonstrates that SMLC protects against atrial remodeling in AF by inhibiting oxidative stress through the mediation of MsrA/p38 MAPK signaling pathway.