Objective To investigate the regulatory effect of Fuling Xingren Gancao granules (FXG) on macrophage polarization in atherosclerosis (AS) model mice. Methods ApoE^-/-mice were used to construct an AS model and RAW264.7 macrophages were used to construct a polarized cell model. The total area of aortic plaques and the degree of aortic stenosis were detected by Oil red O and hematoxylin and eosin staining, respectively. Expression levels of the M1 polarization factors inducible nitric oxide synthase (iNOS) and chemokine ligand 2 (CCL2), as well as the M2 macrophage factors Arg-1, YM1, and CD206, and the phosphorylation levels of signal transducer and activator of transcription (STAT3) in vitro and in vivo were detected by polymerase chain reaction and Western blot. Results FXG significantly reduced the total area of aortic plaques in ApoE^-/-mice, decreased the expression levels of the M1 macrophage polarization factors iNOS and CCL2, and increased the expression levels of the M2 macrophage polarization factors Arg-1 and YM1 (P<0.05). STAT phosphorylation levels were decreased in the model mice and M1 macrophages, but were upregulated after FXG intervention (P<0.05). The STAT3 inhibitor Stattic partially eliminated the regulatory effect of FXG on iNOS and Arg-1 (P<0.05). Conclusions FXG has an inhibitory effect on the progression of AS, via targeting STAT3 to regulate macrophage polarization.