NEDD4 is an E3 ubiquitin ligase containing the HECT domain, which regulates various cellular processes, but its role in vascular endothelial cells is unknown. In the present study, we found that NEDD4 bound directly to XPO1 by co-immunoprecipitation screening. In HUVECs (human umbilical vein endothelial cells), overexpression of NEDD4 reduced Ang II-induced ROS level and cell apoptosis. Ang II stimulation led to nuclear accumulation of cargoes, while overexpression of NEDD4 enhanced the XPO1-dependent nuclear export of its cargoes. KPT185, an inhibitor of XPO1, can abolished the protective effect of NEDD4 under Ang II treatment. In addition, NEDD4 could promote the interaction between XPO1 and RanBP3 via K63-linked ubiquitination of XPO1. These results suggested that NEDD4 played a protective role in vascular endothelial cell injury through regulating XPO1-mediated nuclear export.