Many studies have confirmed that macrophage autophagy injury negatively impacts the pathogenesis of atherosclerosis. Meanwhile, the PI3K/AKT/mTOR signalling pathway affects atherosclerosis progression by regulating macrophage autophagy. We previously reported that the herbal formula San Jie Tong Mai Fang (SJTMF) elicits lipid regulatory and anti-inflammatory properties. Hence, the current study employed an ApoE-/- high-fat diet-fed mouse model to determine whether SJTMF elicits protective effects against atherosclerosis progression via regulation of macrophage autophagy through the PI3K/AKT/mTOR signalling pathway. Our results show that SJTMF reduced the number of atherosclerotic plaques, foam cell formation, and intimal thickness in mouse aorta. In addition, SJTMF improved blood lipid metabolism and inflammatory levels in mice. We also observed that SJTMF caused macrophages to be polarized toward the M2 phenotype via inhibition of the PI3K/AKT/mTOR signalling pathway. Additionally, the abundances of LC3-II/I and Beclin1 proteins—key autophagy molecules—were increased, while that of p62 was decreased, resulting in the promotion of macrophage autophagy. Taken together, these findings indicate that SJTMF may regulate the polarization of macrophages by inhibiting the PI3K/AKT/mTOR signaling pathway, thereby reducing atherosclerotic plaque damage in ApoE-/- mice, thereby, promoting macrophage autophagy and eliciting a significant anti-arteriosclerosis effect. Hence, SJTMF may represent a promising new candidate drug for the treatment of atherosclerosis.