Objective: To study the protective effect and mechanism of D-ribose on Doxorubicin (DOX)-induced cardiotoxicity in mice. Methods: Eight-week-old male ICR mice were randomly divided into normal group (Con), model (DOX) group, D-ribose low-dose group (LDR) and D-ribose high-dose group (HDR), with 10 mice in each group. DOX acute cardiotoxicity mouse model was established by a single intraperitoneal injection of high dose doxorubicin (15 mg/kg). Lactate dehydrogenase (LDH) activity levels in serum and adenosine triphosphate (ATP) content in heart tissue were detected by the commercial kits. The pathological changes of myocardial tissue were observed by hematoxylin-eosin stain (HE) staining. Cardiac oxidative stress was assessed by measuring the activities of total superoxide dismutase (T-SOD), catalase (CAT) and malondialdehyde (MDA) in myocardial tissue. The levels of silent mating type information regulation 2 homolog 1 (Sirt1), peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax) and cysteine-containing aspartate specific protease 3 (Caspase-3) were detected by Western blotting. Results: DOX could significantly reduce the body weight of mice (P