Oxidized low density lipoprotein (ox-LDL)-induced macrophage apoptosis contributes to the formation of atherosclerosis. Metformin, an antidiabetic drug, has been reported to attenuate lipid accumulation in macrophages. In this study, the effects of metformin on ox-LDL-induced macrophage apoptosis were investigated and the mechanisms involved in this process were examined. By performing flow cytometry analysis, it was demonstrated that metformin inhibited ox-LDL-induced macrophage apoptosis. Increased expression of endoplasmic reticulum (ER) stress marker proteins, including C/EBP-homologous protein, eukaryotic translation initiation factor 2A, and glucose-regulated protein 78 kDa, induced by ox-LDL was also reversed by metformin. Furthermore, ox-LDL-induced cytochrome c (cyto-c) release and mitochondrial membrane potential loss were inhibited by metformin. As lipid uptake in macrophages contributed to ER stress, cyto-c release and mitochondrial membrane potential loss, the mechanisms involved in metformin-inhibited macrophage lipid uptake were investigated. Expression of scavenger receptors, including scavenger receptor A, cluster of differentiation 36 and lectin-type oxidized LDL receptor 1 was examined in the presence or absence of metformin with ox-LDL treatment. Additionally, the upstream regulatory mechanism of scavenger receptors by metformin was also analyzed. In conclusion, metformin protects against ox-LDL-induced macrophage apoptosis and inhibits macrophage lipid uptake.