Abstract: Objective: To study the mechanism of quercetin (Que) in improving myocardial injury induced by doxorubicin (Dox) in mice. Methods: Fifty mice were randomly divided into normal group (Control), model group (Dox), quercetin low-dose, medium-dose and high-dose groups (Que-L, Que-M and Que-H), and myocardial injury model was established by intraperitoneal injection of Dox in addition to Control. The cardiac function of mice was evaluated by use echocardiography and hemodynamics, and creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH) levels were detected in serum of mice by ELISA. HE staining, Tunel staining and WGA staining respectively were used to observe the pathological changes of myocardial tissue, myocardial cell apoptosis and myocardial cell cross-sectional area. The expression of p-GSK-3β in myocardial tissue was detected by immunofluorescence, and the expression of PI3K/AKT/GSK-3β pathway and apoptotic protein in mouse myocardial tissue was detected by Western blot. Results: Compared with Control group, left ventricular ejection fraction (LVEF) and left ventricular short axis shortening rate (LVFS) in Dox group were significantly decreased, left ventricular end-diastolic diameter (LVEDd) and left ventricular end-systolic diameter (LVEDs) were significantly increased, and serum CK-MB and LDH contents were extremely significant increased (P<0.01). Cardiomyocytes were swollen and disordered organization. The proteins of PI3K, p-Akt, p-GSK-3β and β-catenin in myocardial tissue were significantly decreased (P<0.01), and the expressions of Bax/Bcl-2 and Cleaved Caspase-3 were extremely significant increased (P<0.01). Compared with Dox group, the myocardial injury of mice in each of Que administration groups were improved to varying degrees, LVEF and LVFS were significantly increased (P<0.01), LVEDd and LVEDs were significantly decreased, serum levels of CK-MB and LDH contents were significantly decreased (P<0.01), and cardiac function was enhanced. The swelling, apoptosis and fibroplasia of cardiomyocytes were reduced, and the proteins expression of PI3K, p-Akt, p-GSK-3β and β-catenin in myocardial tissue were significantly increased (P<0.01), and PI3K/AKT/GSK-3β/β-catenin was activated. The expression of apoptosis proteins Bax/Bcl-2 and Cleaved Caspase-3 were significantly decreased (P<0.01), and the Que-H group had the best therapeutic effect. Conclusions: Que has a certain myocardial protective effect, and can improve Dox induced myocardial injury and apoptosis by activating PI3K/AKT/GSK-3β/β-catenin pathway.