Atherosclerosis is a chronic and progressive disease. Its morbidity and mortality rates have demonstrated an increase in recent years. The present study aimed to explore the role of sirtuin (SIRT) 4 in the development of atherosclerosis. Alterations in SIRT4 expression in response to oxidized low density lipoprotein (oxLDL) were quantified in human umbilical vein endothelial cells (HUVECs) using western blotting. Cell counting kit‑8 and flow cytometry assays were used in order to explore the effects of SIRT4 on HUVEC proliferation and apoptosis. The effect of SIRT4 on the expression of inflammatory factors in HUVECs was analyzed using ELISA. The expression and phosphorylation of proteins in the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt)/nuclear factor (NF)‑κB pathway were comparatively analyzed using western blotting. Nuclear translocation of p65 NF‑κB was examined using immunofluorescence. The present study indicated that oxLDL treatment decreased the expression of SIRT4 in HUVECs in a dose‑ and time‑dependent manner. SIRT4 overexpression promoted oxLDL‑induced HUVEC proliferation and inhibited cell apoptosis. Furthermore, SIRT4 overexpression suppressed the PI3K/Akt/NF‑κB pathway by inhibiting PI3K phosphorylation and phosphorylated (p)‑Akt, p‑nuclear factor of kappa light polypeptide gene enhancer in B‑cells inhibitor α and p‑p65 NF‑κB expression; blocking p65 NF‑κB nuclear translocation and decreasing interleukin (IL)‑1β, IL‑6, and tumor necrosis factor α expression in oxLDL‑induced HUVECs. In conclusion, SIRT4 overexpression enhanced HUVEC survival, suppressed the PI3K/Akt/NF‑κB signaling pathway and inhibited the expression of inflammatory cytokines in oxLDL‑induced HUVECs.