Background: Chronic use of doxorubicin (DOX) as an anticancer and antineoplastic agent has a chief jeopardy of cardiotoxicity. About 10% of the treated population has logged to cause cardiac damage. Objectives: This study principally engrossed on inspecting the effective cardioprotective activity of goniothalamin (GTN) against DOX-induced cardiotoxic rats. Materials and Methods: Group I – control, Group II – inducer (DOX) alone (2.5 mg/kg body weight [BW]) given on alternate days, Group III – DOX + GTN (2.5 mg/kg BW + 200 mg/kg BW), and Group IV – GTN alone (200 mg/kg BW). First, it employed its protective effects over the isolated cardiac tissues in which the status of HO-1 and NQO-1 were upregulated. Results: GTN administered with DOX induced rats were showed the increased the status of antioxidant levels, elevation of reactive oxygen species, which is also reduced the inflammatory and stress markers contributing to its cardio protective activity. Furthermore, GTN also downregulated the mRNA expression status of inflammatory markers and HO-1, NAD (P) H, and NQO-1 in DOX-induced rats, thereby weakening the cardiac damage. Conclusion: GTN is an effective protective agent against DOX-induced cardiotoxicity in rats.