We aimed to study the effects of the new oral anticoagulant edoxaban, a factor X activated (FXa) inhibitor, on key endothelial functions that could contribute to cardiovascular benefit. Human umbilical endothelial cells (HUVEC) were obtained from donated umbilical cords and used to analyse 1) structural functions like cell proliferation, migration, and angiogenesis in appropriate assays; 2) anti-inflammatory reactions as mononuclear cell (PBMC) or platelet adhesion to HUVEC monolayers; and 3) haemostasis control by fibrin formation or plasminogen activator modulation. Key molecular effectors and signalling pathways on each function were explored by profiled protein arrays, mRNA, or protein expression analyses. Edoxaban promoted viability and growth in HUVEC cultures, as well as counteracted the promigratory and antiangiogenic effects of FXa, through action on the PI3K/AKT pathway. Edoxaban inhibited the adhesion to endothelial cells and the transmigration through endothelial monolayers of PBMC, and even counteracted the action of pro-inflammatory stimuli such as FXa by blocking the FXa-induced expression of cell adhesion molecules via the PAR 1-2/PI3K/NF-kB pathway. Haemostatic control of edoxaban could be exerted from the endothelium by the reduction of platelets' adhesion to endothelial cells and the possible acute activation of urokinase plasminogen activator. Edoxaban is a safe and structural stabilizing factor for endothelial cells and also has remarkable anti-inflammatory action, preventing PBMC adhesion and transmigration through the endothelium. It may also contribute to haemostasis control by reducing platelet adhesion. Its main molecular mechanism seems to be the control of the PI3K/NF-κB pathways.