α-Mangostin play crucial role in several cellular progress, including hyperglycemia-induced inhibition of cell growth and promotion of cell apoptosis. Increasing evidence displayed the important roles of lncRNAs and their potential as novel targets for drug development in human disease. However, there is rare study to comprehensively and systematically explore the role and underlying mechanism of lncRNAs in human umbilical vein endothelial cells (HUVECs) under hyperglycemia with or without α-Mangostin. In this study, we firstly found that α-Mangostin reduced the high glucose-induced inhibition of cell proliferation and migration potential of HUVECs. Then, we performed RNA-seq to dissect the expression profiles of lncRNAs in HUVECs treated with high glucose or high glucose supplemented with α-Mangostin. The results showed that the expression of H19 and HE4 was down-regulated by high glucose and further, α-Mangostin restored the high glucose-induced inhibition of H19 and HE4 expression. Further examination demonstrated that the modulation of the H19 and HE4 expression affected the function of α-Mangostin in hyperglycemia. In addition, H19 regulated HE4 expression via the modulation of the miR-140 expression. Finally, we showed that H19 exerted its function via the modulation of H19/miR-140/HE4 in hyperglycemia with α-Mangostin. In summary, this study is the first to comprehensively identify the lncRNAs/mRNAs network in hyperglycemia with or without α-Mangostin, highlighting a novel regulatory pathway in hyperglycemia with or without α-Mangostin and indicating the potential therapeutic role of α-Mangostin in diabetes mellitus.