Aim To investigate the effects of astragalus polysaccharide and hirudin combined intervention on lipid accumulation, mitochondrial membrane potential and apoptosis-related proteins in macrophages induced by oxidized low density lipoprotein (ox-LDL). Methods RAW264.7 cells were incubated with 100 mg/L ox-LDL for 24 h to establish a foam-cell model, which were treated by astragalus polysaccharide and hirudin after dose optimization. The control group, model group, astragalus polysaccharide group, hirudin group and the combined intervention of the two drugs group were established. Oil red O staining and oxidase method were used to detect the cholesterol contents in macrophages induced by ox-LDL, flow cytometry was used to detect the early apoptosis rate, late apoptosis rate and total apoptosis rate of macrophages, the changes of mitochondrial membrane potential were detected by laser confocal microscopy, Western blot was used to detect the expression levels of anti-apoptotic protein Bcl-2, proapoptotic protein Caspase-3 and Bax. Results The contents of cholesterol in macrophages of the astragalus polysaccharide and hirudin combined intervention group were decreased than those in the hirudin group or astragalus polysaccharide group significantly (P＜0.05). Compared with the model group, the astragalus polysaccharide and hirudin combined intervention could reduce the early apoptosis rate and total apoptosis rate of macrophages induced by ox-LDL (P＜0.01), increase the mitochondrial membrane potential of macrophages (P＜0.01), reduce the expressions of Caspase-3 and Bax, and increase the expression of Bcl-2 protein (P＜0.05) significantly. Conclusions The astragalus polysaccharide and hirudin combined intervention in reducing lipid accumulation in macrophages is superior to drug treatment alone. The combined treatment of the two drugs can reduce the apoptosis rate of macrophages induced by ox-LDL. Its mechanism may be related to regulate mitochondrial membrane potential and regulate the expressions of proapoptotic protein Caspase-3, Bax and anti-apoptotic protein Bcl-2.