Doxorubicin (DOX) has a wide antitumor spectrum, but its adverse cardiotoxicity may lead to heart failure. Urotensin II (UII) is the most potent vasoconstrictor in mammals. It plays a role by activating the UII receptor (UT), the orphan G protein-coupled receptor (GPR14), collectively referred to as the UII/UT system. In the new version of "Chinese expert consensus on cardiac rehabilitation of chronic heart failure," it is pointed out that exercise rehabilitation is the cornerstone of cardiac rehabilitation. In this study, in vitro and in vivo assessments were performed using DOX-treated H9C2 cells and rats. It was found that the UT antagonist Urantide and exercise training improved DOX-induced cardiac insufficiency, reduced DOX-induced cardiomyocyte apoptosis, improved the structural disorder of myocardial fibers, and inhibited DOX-induced myocardial fibrosis. Further studies showed that Urantide alleviated DOX-induced cardiotoxicity by downregulating the expression levels of the p38 mitogen-activated protein kinase signaling pathway.