AbstractDoxorubicin (DOX) is a potent chemotherapeutic agent used for cancer treatment, however, DOX‐induced cardiotoxicity is a serious clinical problem because it causes acute and chronic heart dysfunction. Many studies have indicated that the α1‐adrenergic receptor protects the heart from pathologic stress through activation survival signaling, however, the mechanism remains largely unknown. Previous studies have detected that the phenylephrine‐induced complex‐1 (PEX1) transcription factor, also known as zinc‐finger protein 260 (Zfp260), is an effector of α1‐adrenergic signaling in cardiac hypertrophy. Our present study aimed to investigate the role and underlying mechanism of PEX1 in cardiomyocyte survival during DOX‐induced cardiotoxicity. Mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg) to generate DOX‐induced cardiotoxicity. We found that PEX1 expression was downregulated in DOX‐treated murine hearts. PEX1 deficiency resulted in increased apoptosis, and conversely, PEX1 overexpression alleviated apoptosis induced by DOX in primary cardiomyocytes, as well as upregulated antiapoptotic genes such as BCL‐2 and BCL‐XL. Mechanistically, we identified that PEX1 might exert its antiapoptosis effect by playing a pivotal role in the action of α1‐adrenergic signaling activation, which depends on the presence of GATA‐4. Based on these findings, we supposed that PEX1 may be a novel transcription factor involved in cardiac cell survival and a promising candidate target for DOX‐induced cardiotoxicity.