Objective To investigate the effect of Huanglian Huazhuo capsule on diabetic macrovascular disease by regulating peroxisome proliferator-activated receptor γ (PPARγ)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akte) pathway based on histone acetyltransferase (HAT)/histone deacetylase (HDAC) balance. Methods Forty apolipoprotein E (ApoE) gene deleted mice were randomly divided into model group, atorvastatin group, Huanglian Huazhuo capsule group, and atorvastatin+Huanglian Huazhuo capsule group, with 10 in each group. Ten wild-type C57 mice were included in the blank group. The mice in the atorvastatin group were gavaged with atorvastatin at a dose of 10 mg/kg, the mice in the Huanglian Huazhuo capsule group were gavaged with Huanglian Huazhuo capsule aqueous solution at a dose of 0.675 g/kg, the mice in the atorvastatin+Huanglian Huazhuo group were gavaged with atorvastatin at a dose of 10 mg/kg and Huanglian Huazhuo capsule aqueous solution at a dose of 0.675 g/kg, and the mice in the blank group and model group were gavaged with normal saline at the same dose, once daily for 8 weeks. Mouse thoracic aortic smooth muscle cells were collected and divided into blank group, human oxidized low density lipoprotein (ox-LDL) group, ox-LDL+PPARγ silent group, and ox-LDL+PPARγ overexpression group. The blank group was cultured with blank serum, and the other 3 groups were treated with 100 μg/mL ox-LDL, and co-cultured with serum containing 200 μg/mL Huanglian Huazhuo capsule. The ox-LDL+PPARγ silent group was transfected with PPARγ small interfering RNA, and ox-LDL+PPARγ overexpression group was transfected with PPARγ plasmid. Automatic biochemical analyzer was used to detect the blood glucose and blood lipid levels of mice, hematoxylin-eosin staining was used to observe the pathological morphology of mice thoracic aorta, flow cytometry was used to detect the apoptosis rate of smooth muscle cells, and Western blotting and quantitative ploymerase chain reaction were used to detect the protein and mRNA expression of HAT1, HDAC1, PPARγ, PI3K and Akt. Results Compared with the model group, the contents of postprandial blood glucose (PBG), total cholesterol (TC), triglyceride (TG) and low density lipoprotein-cholesterol (LDL-C) of mice in the atorvastatin group, Huanglian Huazhuo capsule group and atorvastatin+Huanglian Huazhuo capsule group were significantly decreased, while the contents of high density lipoprotein-cholesterol (HDL-C) were significantly increased (all P<0.05). Compared with the model group, the inner wall disorder was improved in the atorvastatin group and Huanglian Huazhuo capsule group, and a small number of foam cells were observed. The inner wall of thoracic aorta had the most significant improvement in the atorvastatin+Huanglian Huazhuo capsule group. The apoptosis rate of smooth muscle cells in the ox-LDL+PPARγ silent group was significantly lower than those in the ox-LDL group and ox-LDL+PPARγ overexpression group (both P<0.05). Compared with the ox-LDL group, the expression of HAT1 protein and mRNA in smooth muscle cells of the ox-LDL+PPARγ silent group was significantly increased, while the expression of HDAC1, PPARγ, PI3K and Akt protein and mRNA was significantly decreased (all P<0.05). Compared with the ox-LDL+PPARγ silent group, the expression of HAT1 protein and mRNA in smooth muscle cells of ox-LDL+PPARγ overexpression group was significantly decreased, while the expression of HDAC1, PPARγ, PI3K, Akt protein and mRNA was significantly increased (all P<0.05). Conclusion Huanglian Huazhuo capsule can improve the expression of HDAC1 and the activation of PPARγ/PI3K/Akt pathway by inhibiting the expression of HAT, inhibit the metabolic disorder of mice with diabetic macrovascular disease, increase the apoptosis of smooth muscle cells, and reduce the formation of arterial plaque, displaying a protective role.