T-2 toxin is one of the most potent and commonly occurring secondary metabolites of type A trichothecene mycotoxins. Although it has been associated with cardiomyocyte necrosis, the underlying mechanisms of T-2 toxin-induced myocardial injury, particularly combined with low selenium conditions, remain unclear. This study investigates the role of MLKL, the terminal effector of the Receptor interacting protein kinase-1 and -3/mixed lineage kinase domain-like protein (RIP1-RIP3-MLKL) necroptotic pathway, in cardiac injury induced by T-2 toxin alone or in combination with low selenium. Histopathological analyses revealed that T-2 toxin exposure alone or combined with low selenium significantly exacerbated myocardial lesions, including hemorrhagic foci expansion, interstitial fiber disorganization, and collagen deposition. These structural abnormalities correlated with elevated serum cardiac enzymes (CK, CK-MB, LDH, and AST) and upregulated myocardial expression of TNF-α and IL-6. Immunohistochemical and Western blot analysis revealed a significant increase in the expression of MLKL and phosphorylated MLKL (p-MLKL) following T-2 toxin exposure, both alone and under low selenium conditions. Crucially, Mlkl^-/- mice showed a significant reduction in myocardial enzyme activity, decreased myocardial fibrosis, and lower levels of inflammatory cytokines compared to wild-type mice under both exposure conditions. This study highlights the pivotal role of MLKL-mediated programmed necroptosis in T-2 toxin-induced myocardial injury under both normal and low selenium conditions. Inhibition of MLKL alleviates myocardial damage induced by T-2 toxin exposure alone or combined with low selenium, suggesting that targeting MLKL may serve as a potential therapeutic strategy to mitigate myocardial injury in similar pathological conditions.