Aim To investigate the effect of omentin-1 on the expression of ATP-binding cassette transporter A1 (ABCA1) in macrophages and its mediated cholesterol efflux, as well as to elucidate its regulatory mechanism. Methods After THP-1-derived macrophages incubated with omentin-1 for 24 h, phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) were inhibited and silenced, respectively. Western blot was used to detect protein levels of ABCA1 and liver X receptor α (LXRα), high performance liquid chromatography was adopted to detect total cholesterol (TC), free cholesterol (FC) and cholesterol ester (CE) content, a liquid scintillation counter was applied to determine cholesterol efflux, and intracellular lipid droplets were observed via oil red O staining. In order to explore its mechanism of action in depth, ABCA1-specific siRNA silencing technique was used to observe the effect of omentin-1 on cholesterol efflux. Results Omentin-1 increased the expression of ABCA1 in macrophages in a concentration-dependent manner, promoted cholesterol efflux, reduced the contents of TC, FC and CE in cells, reduced lipid accumulation and inhibited the formation of foam cells. After specifically silencing the expression of ABCA1, the effect of omentin-1 on cholesterol efflux was significantly weakened, the intracellular lipid accumulation was increased, and the formation of foam cells was significantly increased. After inhibiting or silencing PI3K and Akt, the expression of LXR α and ABCA1 was significantly downregulated, the cholesterol efflux effect of omentin-1 was inhibited, the intracellular lipid accumulation increased, and the formation of foam cells increased. Conclusion Omentin-1 can upregulate the expression of ABCA1 in macrophages through PI3K/Akt pathway, enhance cholesterol efflux, thereby reducing lipid accumulation and inhibiting the formation of foam cells.