Diabetes mellitus (DM) is a major risk factor for coronary heart disease (CHD). Previous research has reported that the Fufang-Zhenzhu-Tiaozhi (FTZ) formula has obvious effects on the treatment of dyslipidemia and hyperglycemia. In the present study, we intended to establish a convenient DM-CHD model in minipigs and investigated the protective effect of FTZ against myocardial injury and its mechanism. The DM-CHD model was established by a high-fat/high-sucrose/high-cholesterol diet (HFSCD) combined with balloon injury in the coronary artery. Subsequently, sixteen Wuzhishan minipigs were assigned to three groups: control group, model group, and FTZ group. The model group and FTZ group were given a HFSCD, while the control group was given a normal diet (ND). FTZ was given with meals in the FTZ group. During this time, biochemical parameters, such as total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein (HDL-C), and fasting blood glucose (FBG), were measured by using testing kits. Insulin (INS) was determined by ELISA, and the homeostasis model assessment index of insulin resistance (HOMA-IR) was calculated to evaluate insulin resistance levels. After FTZ administration, the plasma levels of lactate dehydrogenase (LDH), creatine kinase isoenzyme MB (CK-MB), and cardiac troponin I (cTnI) were measured by using ELISA kits to evaluate myocardial injury. Coronary artery stenosis was analyzed by angiographic and HE staining. Myocardial ischemia was assayed with electrocardiogram (ECG). Moreover, cytokines, including interleukin-6 (IL-6), hypersensitive C-reactive protein (hs-CRP), and tumor necrosis factor-alpha (TNF-α), were measured by ELISA kits to assess inflammation. The myocardial tissue was collected, and the pathological morphology was observed by transmission electron microscopy (TEM), HE staining, and Masson staining. Western blots were used to detect the expression of PI3K, AKT, p-AKT, p-NF-κB, and NF-κB. A DM-CHD model in minipigs with glucose-lipid metabolism disorder, coronary artery incrassation and myocardial damage was successfully established through balloon injury in the coronary artery combined with HFSCD. FTZ effectively inhibited coronary artery incrassation and protected the myocardium against injury in DM-CHD minipigs. FTZ decreased proinflammatory cytokine levels and upregulated the protein expression of the PI3K/Akt pathway in the myocardium. A novel DM-CHD model in minipigs was successfully established through balloon injury in the coronary artery combined with HFSCD. FTZ has a protective effect against myocardial injury in DM-CHD by inhibiting inflammation and activating the PI3K/AKT signaling pathway. Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.