Doxorubicin is an anthracycline antibiotic widely used as a chemotherapeutic agent in the treatment of several tumors. However, its cardiac toxicity limits its use at maximum therapeutic doses. Most studies implicated increased oxidative stress as the major determinant of DOX cardiotoxicity. Thevetia peruviana known to have antioxidant activity. The aim of the current study was to explore the potential protective effects of methanolic extract of Thevetia peruviana against DOX-induced cardiotoxicity in rats. Methanolic extract of this plant showed significant cardioprotective effect by lowering the serum levels of various biochemical parameters like Creatinine  phosphokinase (CPK), Lactate dehydrogenase (LDH), Alanine transaminase (ALT) and Aspartate transaminase (AST) in the selected model. Additionally, histopathological examination indicated a protection against DOX-induced cardiotoxicity. The results also suggests that the biologically active phytoconstituents such as flavonoids, alkaloids, glycosides, carbohydrates, triterpenoids and tannins present in the methanolic extract of plant which is confirmed from the qualitative analysis may be responsible for the significant cardioprotective activity.