Inflammation and coagulation are two important processes implicated in venous thromboembolism (VTE). 15-epi-lipoxin A₄ (15-epi-LXA₄) is the epimer of LXA₄, a small lipid molecule, is known to play a key role in the resolution of inflammation. This study aimed to demonstrate whether 15-epi-LXA₄ could suppress the inflammatory factor tumor necrosis factor-alpha (TNF-α)-induced upregulation of tissue factor (TF), an important regulator of the blood coagulation cascade, and evaluated the possible underlying mechanisms. We found that 15-epi-LXA₄ not only reduced the up-regulation of mRNA and antigens, but also lowered the activity of TF (elevated by TNF-α) in primary culture of human umbilical vein endothelial cells (pc-HUVECs). In addition, 15-epi-LXA₄ suppressed the activation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, induced by TNF-α, in pc-HUVECs. 15-epi-LXA₄ also inhibited the binding of NF-κB on the TF promoter, which is otherwise enhanced by TNF-α. The role of 15-epi-LXA₄ in regulating TNF-α-induced effects was enhanced by the PI3K inhibitor and prevented by the PI3K activator. In conclusion, 15-epi-LXA₄ lowered the TNF-α-induced high TF expression and activity by suppressing PI3K/AKT signaling activation, thereby reducing the binding capacity of NF-κB on the TF promoter in pc-HUVECs.