Background <p>Doxorubicin (DOX) is one of the most widespread antibiotics used in the treatment of malignancies. Cardiotoxicity is the main side effect of DOX. Although the protective effects of apigenin have been shown, its mechanisms are still unknown. This study aimed to assess the role of nitric oxide (NO) in the protective effects of apigenin, particularly by altering the expression of connexin 43 (CX43) in the heart tissue.</p> Methods and results <p>In this study, 60 male Wistar rats were divided into six equal groups: control (normal), DOX (2&#xa0;mg/kg every 48&#xa0;h for 12 days i.p.), apigenin (Api, 50&#xa0;mg/kg oral administration), DOX + Api, DOX + L-NAME (Nitro-L-arginine methyl ester) (30&#xa0;mg/kg i.p.), and DOX + Api + L-NAME. Our study assessed alterations in the heart weight and body weight, markers of cardiac function via echocardiography Ejection Fraction (%EF), Fractional Shortening (%FS), Left Ventricular Internal Diameter in Systole (LVIDs), and Left Ventricular Internal Diameter in Diastole (LVIDd), cardiac oxidative stress factors Superoxide Dismutase (SOD), Reduced Glutathione (GSH), Malondialdehyde (MDA), Catalase (CAT), cardiac injury markers Lactate Dehydrogenase (LDH), Creatine Kinase–MB (CK-MB), and Cardiac Troponin I (cTn-I), cardiac fibrosis, and CX43 expression (immunohistochemistry). Apigenin improved cardiac tissue damage and functional parameters such as left ventricular EF. Furthermore, treatment with apigenin, but not DOX, caused a significant reduction in the percentage of cardiac fibrosis and oxidative stress activity. Apigenin can also elevate the cardiac CX43 expression in the DOX + Api compared to the DOX group. NOS inhibition by L-NAME attenuates the protective effects of apigenin in DOX-induced cardiotoxicity</p> Cocclusion <p>Apigenin could exert its cardioprotective effects through an NO-dependent mechanism and elevation of CX43 expression.</p> Graphical abstract <p></p>