Protein polysulfidation occurs at reactive cysteine residues in proteins, which plays pivotal roles in the regulation of redox signaling and mitochondrial bioenergetics. A trace amount of methylmercury (MeHg) is suggested to increase cardiovascular vulnerability, but the underlying mechanism is obscure. We report that exposure to subneurotoxic dose of MeHg caused mitochondrial hyperfission in myocardium through activation of dynamin related protein 1 (Drp1), which precipitated systolic heart failure induced by pressure overload in mice. Treatment of neonatal rat cardiomyocytes (NRCMs) with cilnidipine, an inhibitor of interaction of Drp1 with its guanine nucleotide exchange factor, filamin-A, suppressed MeHg-induced mitochondrial hyperfission. MeHg targeted rat Drp1 proteins at redox-sensitive Cys⁶²⁴, which SH residue was found to make a nucleophilic polysulfidated form. MeHg induced depolysulfidation of Cys⁶²⁴ and mitochondrial hyperfission through filamin-dependent Drp1 activation. Treatment of rat cardiomyocytes with NaHS, a sulfur substrate, significantly suppressed mechanical stress-induced cell death of NRCMs exposed by MeHg. These results suggest that depolysulfidation of Drp1 at Cys⁶²⁴ by low-dose MeHg contributes to increase of cardiac vulnerability to mechanical load via filamin-dependent mitochondrial hyperfission.