Rapamycin (RPM) is frequently used as the drug coating in drug‑eluting stents (DESs) as it can inhibit the growth of smooth muscle cells. However, RPM also inhibits the proliferation and migration of vascular endothelial cells, and impairs reendothelialization in DES implantation. Therefore, the development of a strategy to protect vascular endothelial cells after DES implantation is of great importance. Long non‑coding RNAs (lncRNAs) metastasis‑associated lung adenocarcinoma transcript 1 (MALAT1) and smooth muscle and endothelial cell‑enriched migration/differentiation‑associated lncRNA (SENCR) are able to enhance the proliferation, migration and angiogenesis of endothelial cells, which suggests that they may have potential as antagonists of the adverse effects of RPM in DES. However, the relationship between RPM and lncRNAs in endothelial cells during the intervention is not fully understood at present. The current study investigated the role and potential mechanism of the lncRNA SENCR on the activity of human umbilical vein endothelial cells (HUVECs) after RPM treatment. The proliferation, migration, angiogenic capacity and cell cycle progression of lncRNA SENCR‑overexpressing HUVECs following RPM treatment was examined. The proliferation‑related proteins of lncRNA SENCR‑modified HUVECs were evaluated to understand the mechanism of action. LncRNA SENCR significantly alleviated the inhibition of proliferation, migration, angiogenesis and cell cycle progression of HUVECs caused by RPM by activating extracellular signal‑regulated kinase 1/2 and mammalian target of RPM. The lncRNA SENCR could alleviate the inhibitory effects of RPM on HUVECs and may be useful as a new combinative agent to avoid the disadvantages of RPM in DES implantation.