Liver X receptor alpha (LXRα) plays important roles in lipid metabolism and inflammation. Therefore, it is essential for protection against atherosclerosis (AS). In AS plaques, the key cells involved in lipid metabolism and inflammation are macrophages. However, the mechanism by which LXRα regulates macrophage involvement in AS formation remains unclear. In this study, we first confirmed the effects of an LXRα agonist (T0901317) and antagonist (GSK2033) on foam cell formation and inflammation in vivo and in vitro. Indeed, T0901317 reduced the number of macrophages in AS plaques and decreased the number of migrated macrophages, as assessed using an in vitro transwell assay. Next, we investigated the relationship between the reduction in macrophages in AS plaques and cytokine levels or foam cell formation. The results show that T0901317 reduced the number of high cholesterol-induced M1 macrophages by converting them into M2 macrophages in vivo and in vitro. Due to this phenotypic transition of macrophages, the inflammatory response was alleviated, and lipid metabolism was enhanced in AS plaques. This effect was achieved by promoting the expression of reverse transporters (ATP-binding cassette transporter member 1 and ATP-binding cassette subfamily G member 1) and inhibiting the phosphorylation of nuclear factor-κB-mediated phosphorylation.