BACKGROUND: Apatinib is a tyrosine kinase inhibitor used for targeted cancer therapy, but its cardiovascular toxicity, particularly hypertension, limits its clinical application. We observed significant mitochondrial fragmentation in endothelial cells after apatinib treatment. This study aims to investigate the role of endothelial mitochondrial fission mediated by Drp1 (dynamin-related protein 1) in apatinib-induced hypertension. METHODS: We established an apatinib-targeted gastric cancer–bearing nude mice model. Apatinib was also administered to human umbilical vein endothelial cells in vitro. Mitochondrial morphology changes in endothelial cells were examined. The role of Drp1 in this process was validated using various experimental methods.