Objective To investigate the mechanism by which Fuling Xingren Gancao Decoction stabilizes vulnerable atherosclerotic plaques. Methods A mouse model of atherosclerosis and a smooth muscle cell lipid accumulation model were established. Histopathological changes in mouse tissues were examined by hematoxylin and eosin(HE), Sirius red, and immunofluorescence staining. Lipid deposition in mice and cells was assessed by oil red O staining. Expression levels of ATP-binding cassette transporter (ABC A1) and ABCG1 mRNA, and diacylglycerol O-acyltransferase 2 (DGAT2) in mice and cells were measured by RT-qPCR and Western blot. Results Compared with ApoE^{- / -} model mice, α-smooth muscle actin (SMA) (P<0. 05) and collagen levels (P<0. 05) and fibrous cap thickness (P<0. 001) were significantly increased in plaques in FXG group, while the lipid necrotic core area (P<0. 001), matrix metalloproteinase (MMP) 2 (P<0. 01) and DGAT2 contents (P<0. 01), and lipid deposition in the aortic root and liver tissue were decreased (P<0. 01,P<0. 001). The decoction also significantly reduced the DGAT2 content (P<0. 01) and lipid deposition in smooth muscle cells and increased ABCA1 (P<0. 05) and ABCG1 mRNA levels in cells in vitro ( P< 0. 01 ). Conclusions Fuling Xingren Gancao Decoction stabilizes vulnerable atherosclerotic plaques by reducing lipid accumulation via regulating DGAT2 expression.