Sorafenib is an oral multi-kinase receptor inhibitor that targets various signaling pathways. It is used as the first line of treatment in advanced hepatocellular and renal cell carcinomas. Sorafenib was reported to induce cardiotoxicity due to myocyte necrosis. Hesperetin is a naturally occurring flavonoid with antioxidant and anti-inflammatory capabilities. This study investigated the putative protective effect of hesperetin against sorafenib-induced cardiotoxicity in mice through downregulation of NLRP3/TLR4 signaling and inhibition of apoptosis. Twenty-four male Swiss mice were distributed into four groups: untreated control, hesperetin (50 mg/kg/day, orally), sorafenib (100 mg/kg/day, orally), and combination (Hesperetin+Sorafenib). After a three-week treatment period, various biochemical parameters in cardiac tissues were assessed. TNF-α, IL-1β, and IL-6 levels were measured. Moreover, TLR4 and NLRP3 expressions were evaluated using Western blot analysis. Histopathological examination and immunohistochemical assessment of apoptotic activity were done. Compared with the sorafenib group, the combination group exhibited reduced TNF-α, IL-1β, IL-6 levels and lower NLRP3/TLR4 expressions. Histologically, the combination group showed improved myocardial histology and a marked decrease in collagen deposition. Immunohistochemical examination showed decreased caspase-3 and increased Bcl-2 expression. Before recommending hesperetin as an adjuvant, clinical studies are warranted for mitigating sorafenib cardiotoxicity.