Cardiotoxicity restricts the clinical use of anthracyclines. Although recent evidence indicates that aberrant activation of the cytosolic DNA-sensing pathway mediates cardiotoxicity, the function of extracellular DNA remains unclear. Here we observe a substantial increase in circulating neutrophil extracellular trap (NET) DNA in individuals with lymphoma experiencing cardiotoxicity after anthracycline-containing treatment. Using mouse models and human organotypic myocardial slices, we demonstrate that doxorubicin induces HMGB1-dependent cardiac NET formation, thereby promoting cardiac remodeling and dysfunction. Mechanistically, extracellular NET DNA is recognized by the transmembrane protein CCDC25 on cardiomyocytes, and their cross-talk generates reactive oxygen species and activates autophagic flux, subsequently impairing cardiac function. Targeting CCDC25 significantly alleviates anthracycline cardiotoxicity and synergizes with the antitumor efficacy of doxorubicin in lymphoma and breast cancer models. Overall, our findings demonstrate a previously unrecognized role of NETs and CCDC25 in anthracycline cardiotoxicity and suggest that targeting CCDC25 could provide a dual therapeutic and cardioprotective advantage.