Filamin B (FLNB) is a cytoskeletal protein known to bind actin filaments and link the cell membrane to the cytoskeleton to coordinate extracellular stimuli and intracellular effectors. Mutations in FLNB are linked to skeletal dysfunction, whereas truncated FLNB impairs microvascular development. We have identified a novel interaction between FLNB and histone deacetylase 7 (HADC7), a member of class IIa histone deacetylase critical for the maintenance of blood vessel integrity. We found that monoubiquitination of FLNB plays a key role in vascular endothelial growth factor (VEGF)-mediated cytoplasmic sequestration of HDAC7 in endothelial cells (ECs). We have further mapped a KVG tripeptide (K1147, V1148, and G1149) in immunoglobulin-like repeat 10 (R10) of FLNB that is essential for its monoubiquitination. Importantly, we discovered that FLNB is a negative regulator of VEGF-mediated EC migration and capillary tube formation. This inhibition is mediated, in part, by promoting VEGF-induced degradation of VEGF receptor 2 (VEGFR2), presumably through a physical association between FLNB and VEGFR2. Taken together, we have demonstrated that FLNB regulates EC behavior by regulating the VEGF-mediated nucleocytoplasmic shuttling of HDAC7 and by promoting VEGF-induced VEGFR2 protein degradation.