Endothelial cell dysfunction and inflammatory responses are important early contributors to the occurrence and development of atherosclerosis (AS), which still remains to be decoded. Ubiquitin-fold modifier 1 (Ufm1) is a new member of the ubiquitin-like protein family, and its biological function remains largely unknown, particularly in endothelial cell injury and inflammatory responses. In the present study, we showed that Ufm1 was highly expressed in both the nucleus and cytoplasm of human umbilical vein endothelial cells (HUVECs). We also demonstrated that the Ufm1 expression level was increased following lipopolysaccharide (LPS)‑induced inflammation in HUVECs. Moreover, overexpression of Ufm1 in HUVECs alleviated the inflammatory responses induced by LPS treatment. Additionally, we found that Ufm1 overexpression inhibited the nuclear translocation of nuclear factor-κB (NF-κB) after LPS treatment, suggesting its implication in the LPS/Toll-like receptor 4 (TLR4)/NF-κB pathway. Taken together, in addition to decoding its expression pattern in endothelial cells, we showed for the first time that Ufm1 is upregulated in LPS-induced inflammation and Ufm1 plays an inhibitory role in inflammatory responses by targeting NF-κB nuclear translocation. Thus, Ufm1 may be a novel gene that protects against inflammatory responses.