The most common feature of endothelial dysfunction is endothelial inflammation. A bunch of factors are associated with endothelial dysfunction. These include pro-inflammatory cytokines, cell adhesion molecules, and matrix degrading enzymes. SIRT4, a member of the sirtuin family, is a mitochondrial ADP-ribosyltransferase. The roles of SIRT4 in regulating inflammation in endothelial cells are unknown. In this study, we found that lipopolysaccharide treatment decreased the expression of SIRT4 in human umbilical vein endothelial cells. Silence of SIRT4 exacerbated the expression of pro-inflammatory cytokines (IL-1β, IL-6 and IL-8), COX-prostaglandin system (COX-2), ECM remodeling enzymes MMP-9, and the adhesion molecule ICAM-1. The upregulation of these genes are involved in inflammation, vascular remodeling, and angiogenesis. In contrast, overexpression of SIRT4 attenuated the induction of these factors. Mechanistically, SIRT4 was found to interfere with the NF-κB signaling pathway by preventing NF-κB nuclear translocation and thereby has an anti-inflammatory function. Loss of SIRT4 increased the nuclear translocation as well as the transcriptional activity of NF-κB. However, overexpression of SIRT4 mitigated the nuclear translocation and the transcriptional activity of NF-κB. Our data suggested that SIRT4 might be a potential pharmacological target for inflammatory vascular diseases.