Cardiovascular disease (CVD) is recognized as a major and increasing health problem affected older subjects in China, and clopidogrel has been widely used for treatment of CVD patients such as atherosclerosis, myocardial infarction, and myocardial ischaemia-reperfusion damage. However, the molecular mechanisms of clopidogrel for treatment of CVD are only partially understood. This study investigated the effects of clopidogrel on palmitic acid-induced damage of human vascular endothelial cells (HUVECs), and the molecular mechanisms of LncRNA HIF1A-AS1 in regulating the proliferation and apoptosis of HUVECs in vitro. We firstly established a damage model of HUVECs through palmitic acid (PA) treatment. And the effect of clopidogrel reducing PA-induced apoptosis of HUVECs was observed by the flow cytometric measurement. To further understand the molecular mechanism of clopidogrel rescues PA-induced apoptosis, we used human LncRNA PCR array to compare the LncRNA expression profile difference between clopidogrel-treated cells and control cells. The expression of LncRNA HIF 1 alpha-antisense RNA 1 (HIF1A-AS1) was significantly altered in clopidogrel-treated cells. We further proved that suppression of HIF1A-AS1 by siRNA reduce PA-induced apoptosis and promote proliferation of HUVECs. Furthermore, we also demonstrated inhibition apoptosis effect by HIF1A-AS1 is related to mitochondrial apoptosis pathway. Hence, our results suggest that clopidogrel rescues apoptosis and promotes proliferation of PA-induced damage model of HUVECs through inhibiting the mediator LncRNA HIF1A-AS1. These findings indicate that LncRNA HIF1A-AS1 may play an important role in the pathogenesis of CVD, and provide a novel molecular mechanism of clopidogrel for treatment of CVD.