Angiogenesis, the sprouting of neovasculature from established vessels, is an essential biological process for wound healing, embryonic development and disease progression in patients with malignancies and diabetic ocular complications. In this study, we investigated the role of CEP78, a centrosomal protein, in regulating endothelial cell function and angiogenesis. We utilized various molecular methods, including siRNA-mediated knockdown, immunofluorescence, quantitative PCR and Western blotting to explore the impact of CEP78 on endothelial cell proliferation, migration, invasion, spindle orientation, microtubule stability and centrosomal function. Our results demonstrated that CEP78 knockdown significantly impaired endothelial cell proliferation, migration, invasion and tube formation. Furthermore, we observed disruptions in spindle orientation and microtubule dynamics, with altered centrosomal localization of key microtubule-associated proteins such as p150glued. CEP78 was found to interact with p150glued, thereby influencing microtubule stabilization and centrosome function and ultimately affecting endothelial cell behavior during angiogenesis. In conclusion, our data demonstrate that CEP78 exerts a pivotal regulatory influence on vascular endothelial activity and is a novel therapeutic candidate for angiogenesis-dependent pathologies.