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Endothelial cell injury is a key factor in the spread of infection and pathogenicity of Treponema pallidum. The migration and adhesion reaction mediated by T. pallidum lipoprotein plays an important role. This study aimed to systematically explore the migration and adhesion effect of T. pallidum lipoprotein Tp0768 and its molecular mechanism. Stimulating vascular endothelial cells with Tp0768 increased the expression of ICAM‐1, MCP‐1, and IL‐8. Moreover, it promoted the migration and adhesion of THP‐1 cells to vascular endothelial cells. Our results revealed that Tp0768 promoted the THP‐1 cells migrating and adhering to vascular endothelial cells by the PERK and IRE‐1α pathways of endoplasmic reticulum (ER) stress. We further demonstrated that the inhibition of the NF‐κB pathway and the downregulation of hypoxia‐inducible factor 1 alpha (HIF‐1α) reduced the mRNA levels of ICAM‐1, MCP‐1, and IL‐8 induced by Tp0768. Also, the adhesion rate of THP‐1 cells to endothelial cells decreased. After inhibiting ER stress, NF‐κB p65 nuclear translocation was weakened, and the mRNA level of HIF‐1α was also significantly downregulated. Our results indicated that T. pallidum lipoprotein Tp0768 promoted the migration and adhesion of THP‐1 cells to vascular endothelial cells through ER stress and NF‐κB/HIF‐1α pathway.