The primary aim of this study was to find the potential modulatory roles of quercetin (QUE) against Adriamycin (ADR)-induced cardiotoxicity. A total of 50 rats were assigned to five groups: a control group, an ADR-treated group, a QUE-treated group, a prophylaxis-cotreated group, and a therapeutic-cotreated group, respectively. QUE exhibited a significant cardioprotective effect, particularly, when it was administered prior to and concurrently with ADR treatment (prophylaxis-cotreated group). This effect was biochemically evident by the significant decreases in the serum levels of myocardial injury biomarkers such as troponin, creatine kinase-myocardium bound, and creatine phosphokinase. In addition, significant elevations in myocardial antioxidant indices coupled with significant reductions in myocardial malondialdehyde contents and DNA damage, elicited by ADR injection, were observed. All these biochemical improvements were accompanied by a significant histopathological recovery and obvious modulation of the AMP-activated protein kinase (AMPK) signaling pathway by promoting the expression of the AMPKα2, PPARα, and PCG-1α genes. Taken together, these findings conclusively showed that QUE administration through its antioxidant capacity and myocardial energy metabolism restoration provides a prophylactic effect in response to ADR-induced deleterious effects, in the rat heart.