This study aimed to determine the cardioprotective effect of necrosulfonamide (NSA), a pyroptosis and necroptosis inhibitor, against acute doxorubicin cardiotoxicity. Fifteen male mice were divided into three groups (n=5/group). Cardiotoxicity was induced by a single intraperitoneal injection of 20 mg/kg of DOX on the 3^rd day of the experiment. The control group received daily intraperitoneal (i.p.) injections of 5% DMSO for five consecutive days. The second group, the DOX group, received a single i.p. injection of 20 mg/kg DOX on the third day of the experiment. The third group, the DOX plus necrosulfonamide (NSA) group, received DOX injections like the second group and 5 mg/kg of NSA i.p. daily for five days, starting two days before the DOX injection. At the end of the study, animals were euthanized, and blood and tissue samples were collected. Various parameters, including cardiac troponin I (cTnI), TNF-α, IL-1β, caspase-1, glutathione peroxidase-4 (GPX-4), and hemeoxygenase 1 (Hmox-1), were measured using ELISA. Cardiac expression of the NF-κB gene was determined by RT-qPCR. A histopathological assessment of myocardial lesions was also performed. DOX administration significantly increased serum cTnI levels and tissue inflammatory biomarkers (TNF-α, IL-1β, caspase-1) while reducing tissue antioxidant enzymes (GPX-4, Hmox-1). In addition, it significantly increased nuclear factor-κB (NF-κB) gene expression compared to the control (about 10.5-fold elevation). Histopathological analysis revealed marked vacuolization and necrosis. However, pretreatment with NSA dramatically altered these findings, with serum cTnI levels significantly lower in this group compared to DOX. Inflammatory indicators decreased, and antioxidant enzymes were restored to varying degrees. NSA pretreatment downregulated NF-κβ gene expression and preserved near-normal myocardial morphology. Our results showed that NSA protected against DOX-induced cardiotoxicity, an effect likely mediated by its anti-pyroptotic, anti-necroptotic, and antioxidant properties.