Atherosclerosis is the major cause of myocardial infarction and stroke, which is a leading cause of morbidity and mortality in developed countries. During the pathological process of atherosclerosis, inflammation participates in all stages of atherosclerosis. Tumor necrosis factor-α (TNF-α), one of the most important inflammatory factor, induces apoptosis of endothelial cells, which play a central role in endothelial dysfunction. However, the underlying mechanism involved in long noncoding RNA (lncRNA) remains unclear. In the present study, we demonstrated the role of lncRNA highly upregulated in liver cancer (HULC) in TNF-α-induced apoptosis. HULC expression was decreased with TNF-α treatment. Restoring HULC expression rescued the apoptosis induced by TNF-α. HULC regulated TNF-α-induced apoptosis through regulation of miR-9 expression. Furthermore, RNA immunoprecipitation and RNA pull-down assays showed that HULC modulated miR-9 expression through association with DNA methyltransferases and suppression of miR-9 expression. HULC-miR-9 pathway may be a potential target for treating atherosclerosis.