Doxorubicin (DOX) is an effective anthracycline agent used to combat many neoplastic diseases. However, DOX causes cardiovascular toxicity in juvenile and young adult cancer survivors that can lead to future cardiomyopathy. Thus, it is essential to address the cardiovascular toxicity caused by DOX to improve the long-term health of cancer patients. Several studies have suggested that soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) are implicated in cardiovascular diseases by impairing vascular health and promoting the transition of Endothelial cells to Mesenchymal cells (EndMT). Given the role of sEH and COX-2 in EndMT cardiovascular toxicity, we aimed to investigate the effect of a dual sEH/COX-2 inhibitor, PTUPB, on DOX-induced EndMT, vascular and cardiac toxicity. We tested the beneficial effect of PTUPB on DOX-induced cardiovascular toxicity in zebrafish.