Aim The purpose of the present study was to investigate the potential role and mechanism of mitogen activated protein kinase kinase kinase kinase 4 (MAP4K4) in human umbilical vein endothelial cell (HUVEC) injury induced by oxidized low density lipoprotein (ox-LDL). Methods The cell injury model was induced by ox-LDL (100 mg/L). The mRNA expression of MAP4K4 was detected using RT-PCR assay. Western blot analysis was conducted to estimate the protein levels of MAP4K4, Bax, Bcl-2, C-Caspase-3, peroxisome proliferators-activated receptorγ (PPARγ) and ATP binding cassette transporter A1 (ABCA1). CCK8 assay was performed to measure cell viability. ELISA assay was applied to analyse cell apoptosis. The reactive oxygen species (ROS) production was measured by DCFH-DA assay.The content of malondialdehyde(MDA) and the activity of superoxide dismutase (SOD) and catalase (CAT)were detected by commercially available assay kits. Results The expression of MAP4K4 was elevated in ox-LDL-stimulated HUVEC. In addition, silencing of MAP4K4 apparently enhanced cell viability and attenuated HUVEC apoptosis induced by ox-LDL accompanied by a decrease in the expression of Bax and C-Caspase-3 and an increase in the expression of Bcl-2. Moreover, MAP4K4 knockdown remarkably alleviated the generation of ROS and the content of MDA accompanied with the enhanced activity of anti-oxidative enzyme system SOD and CAT triggerd by ox-LDL. Mechanically, ablation of MAP4K4 obviously activated PPARγ/ABCA1 signaling pathway. Conclusion Depletion of MAP4K4 relieves ox-LDL-induced vascular endothelial injury by reducing apoptosis and mitigating oxidative damage via PPARγ/ABCA1 activation, thus providing the basis for the therapeutic effect of MAP4K4 on the As.