The clinical use of the anticancer drug doxorubicin (DOX) is limited due to its time- and dose-dependent cardiotoxicity. Therefore, there is an urgent need to explore the molecular mechanism and coping strategies for alleviating DOX-induced cardiotoxicity (DIC) and solve the difficulties in clinical application. The role and mechanism of androgen receptor (AR), which is the target of androgen, in DIC remain unclear. Here, we elucidated the molecular mechanisms of AR in DOX-induced cardiotoxicity. Inhibition of AR aggravated the DOX-induced cardiac function impairment, while the activation of AR showed obvious therapeutic effect and rescued cardiac function of rats. AR can physically interact with SERCA2a. Activation of AR participates in the regulation of DOX-induced myocardial injury by modulating SERCA2a, attenuating DOX-induced endoplasmic reticulum stress, improving calcium (Ca