Cardiac dysfunction is one of the major causes of mortality and morbidity throughout the world. Chronic exposure of arsenic (As) mainly leads to cardiotoxic effect. Cardiotoxicity was induced by the sodium arsenite as the source of As (5 mg/kg BW, PO) for 4 weeks. As intoxication significantly (p < 0.05) increased the serum cardiac markers, viz. creatine kinase-MB, lactate dehydrogenase, aspartate transaminase, alanine transaminase and alkaline phosphatase, oxidative stress markers in heart, plasma total cholesterol (TC), triglycerides (TG), phospholipids (PL), free fatty acids (FFA), low density lipoprotein cholesterol, very low density lipoprotein cholesterol as well as cardiac lipid profile (TC, TG and FFA) and significantly (p < 0.05) decreased the level of serum high density lipoprotein cholesterol, cardiac PL, mitochondrial enzymes such as ICDH, SDH, MDH, α-KDH and NADH dehydrogenase, levels of enzymatic antioxidant, nonenzymatic antioxidants and membrane-bound ATPases in heart. In addition, As-intoxicated rats showed a significant (p < 0.05) up-regulation of myocardial NADPH (NOX) oxidase sub units such as NOX2 and NOX4 as well as Keap-1 and down-regulation of Nrf2 and HO-1 protein expressions. Pre-administration of silibinin (SB) (75 mg/kg BW) remarkably recovered all these altered parameters to near normalcy in As-induced cardiotoxic rat. Moreover, the light microscopic and transmission electron microscopic study further supports the protective efficacy of SB on the heart mitochondria. In conclusion, our data demonstrate that SB has a potential to extenuate the arsenic-induced cardiotoxicity and dyslipidemia in rat.