This research aims to probe the effect and mechanism of microRNA-138-5p (miR-138-5p) in regulating oxidized low-density lipoprotein (Ox-LDL)-induced lipid peroxidation of vascular endothelial cells (VECs). The miR-138-5p profile in the serum of 50 atherosclerosis (AS) patients and 50 healthy donors was compared by reverse transcription-polymerase chain reaction (RT-PCR). VECs were treated with Ox-LDL to construct a model of lipid peroxidation injury in vitro. miR-138-5p mimics and inhibitors or the corresponding negative controls were transfected into VECs. CCK-8 and BrdU methods were used to detect the viability of VECs. RT-PCR and Western blot (WB) were implemented to test inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6), SIRT1, COX2, iNOS, STAT6, NF-kappa B, Caspase3, Bcl2, Bax, MMP3, MMP9, ICAM1, VCAM1, and LOX1, respectively. Moreover, the relevancy between miR-138-5p and SIRT1 was validated by bioinformatics analysis and further testified by dual-luciferase reporter assay. As the data indicated, miR-138-5p was up-regulated in the serum of AS patients and exhibited a positive correlation with the plasma LDL level. In vitro, overexpressing miR-138-5p promoted Ox-LDL-mediated VECs apoptosis, inhibited cell viability and angiogenesis, aggravated inflammation, attenuated the expression of STAT6 and promoted NF-kappa B pathway activation, whereas miR-138-5p inhibition exerted the opposite effects. Mechanistically, miR-138-5p targeted the 3'untranslated region (3'-UTR) of SIRT1 and negatively regulated SIRT1. Moreover, knocking down SIRT1 distinctly reversed miR-138-5p inhibitor-mediated anti-apoptosis and anti-inflammatory effects against Ox-LDL. Collectively, inhibiting miR-138-5p attenuated Ox-LDL-modulated VEC injury and inflammation by regulating the SIRT1/NF-.B pathway.