Endothelial-cell (EC) apoptosis serves a vital role in the pathogenesis of atherosclerosis. Accumulating evidence has implicated microRNA (miRNA/miR) dysregulation in EC apoptosis. Although the role of miR-454-3p in carcinogenesis has been well documented, its role and underlying mechanism in EC apoptosis remain unclear. In the present study, the results revealed that miR-454-3p expression was substantially downregulated in human aortic endothelial cells (HAECs) following oxidized low-density lipoprotein (ox-LDL) treatment. miR-454-3p suppression significantly attenuated the viability of HAECs, while miR-454-3p overexpression repressed ox-LDL-induced HAEC apoptosis. Bioinformatics analysis and luciferase reporter assays revealed that transient receptor potential canonical 3 (TRPC3), a key regulator of atherosclerosis development, was the direct target of miR-454-3p. Furthermore, TRPC3 overexpression abolished the anti-apoptotic effect of miR-454-3p on HAECs. These results revealed a novel role of miR-454-3p in ox-LDL-induced apoptosis in HAECs.