Aim To analyze the expression of miR-29c-5p in peripheral blood leukocytes of patients with coronary heart disease (CHD), and to explore its mechanism in regulating oxidative damage and apoptosis of endothelial cells induced by high-lipid conditions. Methods The expression levels of miR-29c-5p were detected in peripheral blood leukocytes of patients with CHD. Endothelial cell injury in EA.hy926 cells was induced by exposure to high concentrations of the lipid. miR-29c-5p was overexpressed and silenced respectively in the high-fat-induced model, and the expression of apoptosis-related proteins, the level of reactive oxygen species (ROS), and the degree of lipid peroxidation were detected. Bioinformatics methods were used to predict the potential target genes of miR-29c-5p, and the dual luciferase reporter assay was performed to verify its regulatory relationship with the target genes. Results Compared with the control group, the expression level of miR-29c-5p was decreased in the CHD group and had diagnostic significance for CHD with an AUC value of 0.712 (95%CI:0.632～0.792, P＜0.01). In the high-fat-induced model, cell viability was decreased and cell apoptosis was increased (P＜0.01), together with an elevated miR-29c-5p expression level (P＜0.01).Silencing miR-29c-5p expression alleviated cell damage, increased cell viability (P＜0.01), reduced hight-fat-induced apoptosis, lowered ROS and lipid peroxidation levels (all P＜0.05); while overexpressing miR-29c-5p decreased cell viability (P＜0.01), increased high-fat-induced cell apoptosis and raised ROS and lipid peroxidation levels (all P＜0.05). Moreover, bioinformatics analysis prediction and dual luciferase reporter assay confirmed that miR-29c-5p bound to the 3′UTR region of the histonedeacetylase 2 (HDAC2) gene, thereby downregulating the mRNA and protein expression levels of HDAC2 (all P＜0.05). Conclusion The expression of miR-29c-5p is decreased in peripheral blood leukocytes of patients with CHD, which may serve as a diagnostic biomarker for this disease. Inhibition of miR-29c-5p expression in endothelial cells may alleviate oxidative injury and apoptosis induced by high-fat exposure via upregulating HDAC2.