Methylmercury (MeHg) is an electrophilic environmental neurotoxicant that is biologically concentrated into seafood. High-dose MeHg exposure leads covalent modification of protein thiol groups to form S-mercuration (MeHg-S-protein). This pathological protein modification, in part, explains the neurotoxicity of MeHg. Epidemiological studies have also suggested that MeHg increases cardiac risk at a lower concentration than that associated with neurotoxicity. However, the underlying mechanism is unclear. We previously identified that aberrant mitochondrial fission induced by hypoxic stress cause cardiac vulnerability. Here we show that exposure to a low dose of MeHg increased cardiac risk induced by pressure overload in mice. MeHg exposure caused mitochondrial hyperfission in myocardium through the activation of mitochondrial fission factor Drp1. MeHg treatment promoted Drp1 activation by increasing the interaction between Drp1 and its guanine nucleotide exchange factor filamin A. Modification of cysteine residues in proteins with polysulfides play an indispensable role in redox signaling and mitochondrial homeostasis in mammalian cells. Drp1 activity was negatively regulated by polysulfidation at Cys624, a redox-sensitive residue. MeHg exposure induced the depolysulfidation of Cys624 in Drp1, which led to filamin A-dependent activation of Drp1 and mitochondrial hyperfission. Other environmental pollutant, cigarette sidestream smoke that is a significant contributor to increased cardiovascular mortality also led cardiomyocyte dysfunction through Drp1 depolysulfidation. Treatment with NaHS, which acts as a donor for reactive polysulfides, reversed MeHg-evoked Drp1 depolysulfidation and vulnerability to mechanical load in rodent and human cardiomyocytes and mouse hearts. These results suggest that depolysulfidation of Drp1 at Cys624 by environmental stress such as MeHg increases cardiac fragility to mechanical load through filamin-dependent mitochondrial hyperfission.