Background: Doxorubicin (DOX) is commonly used for treatment of hematologic and solid malignancies but its dose related cardiotoxicity limits its use. Therefore, this study aims to evaluate the possible protective effect of Hypericum perforatum (HP) against doxorubicin cardiotoxicity. Methods: Rats were allocated into 4 groups: GI: received normal saline i.p.; GII: received DOX (15 mg/kg; single i.p. injection); GIII: received HP 125 mg/kg/day p.o for 3 weeks + DOX; GIV: received HP 250 mg/kg/day p.o. for 3 weeks+ DOX. ECG was performed then the animals were sacrificed. Sera were collected for estimation of LDH, CK-MB and cTnT. Hearts were isolated for histopathological examination and determination of APN, adiponectin receptor 1, adiponectin receptor 2, AMPKα1, AMPKα2, GSH, and MDA. SOD and catalase activities besides, the gene expression of BCL2, Bax and caspase 3 were also determined. Results: Dox induced bradycardia, widening of QRS complex and prolongation of PR intervals, increased serum LDH, CK-MB and cTnT, and promoted cardiomyocyte inflammation and apoptosis. Additionally, Dox increased Bax and caspase 3, while decreasing BCL2 gene expression. Meanwhile, cardiac GSH, SOD, CAT, and GPx were decreased along with elevation of MDA. Furthermore, Dox decreased cardiac Adiponectin (APN), adiponectin receptor 1, adiponectin receptor 2, AMPKα1 and AMPKα2 gene expression. On the other hand, pretreatment with HP improved all the aforementioned parameters in a dose dependent fashion, with amelioration of cardiomyocyte inflammation and apoptosis compared with DOX group. Conclusions: HP protects against DOX cardiotoxicity via enhancement of cardiac adiponectin-AMPK signaling.