The therapeutic effect of sacubitril/valsartan (S/V) on heart failure has been confirmed, while its role in atherosclerosis remains largely unexplored. The present study aimed to investigate the effects of S/V on the expression of metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), inflammation and apoptosis in human umbilical vein endothelial cells (HUVECs) induced by oxidized low-density lipoprotein (ox-LDL) and to elucidate its possible mechanism. Cell Counting Kit-8 assay was used to detect cell viability. Reverse transcription-quantitative PCR was performed to detect the MALAT1 expression. ELISA was performed to detect the levels of IL-1β, IL-6 and TNF-α. Flow cytometry was conducted to detect the apoptotic rate of cells. A nitric oxide (NO) detection kit was used to determine the concentration of NO. Western blotting analysis was performed to determine the levels of intercellular cell adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, endothelin-1, caspase-3, Bax, Bcl-2, Toll-like receptor 4 (TLR4), p65 and p-p65. Compared with the ox-LDL group, S/V treatment significantly increased the cell viability, NO concentration and Bcl-2 expression, decreased the levels of IL-1β, IL-6 and TNF-α and reduced the expressions of MALAT1, ICAM-1, VCAM-1, cleaved-caspase-3, Bax, TLR4 and p-p65. Overall, the findings suggested that S/V could downregulate the expression of MALAT1, inhibit inflammation and apoptosis and improve endothelial function in ox-LDL-induced HUVECs via inactivating the TLR4/NF-κB signaling pathway. Therefore, S/V might be utilized as a promising therapeutic strategy for the prevention and treatment of atherosclerosis.