Objective To investigate and compare the protective effects of three classic Mongolian medicines, Danggong-3 (DG-3), Zandan-3 (ZD-3), and Zadi-5 (ZD-5), on myocardial ischemia-reperfusion injury (MIRI) in mice. Methods Seven-week-old male C57BL / 6 mice were divided randomly into six groups: sham operation, model, compound Danshen dropping pills (positive control), DG-3, ZD-3, and ZD-5 groups. The mice were administered drugs by gavage 14 days before modeling. The model was established using the reversible left anterior descending coronary artery ligation method, and the electrocardiogram ST segment was monitored continuously. Mice in all groups underwent 20 minutes of ischemia, followed by euthanasia at either 24 hours or 7 days post-reperfusion. The MIRI modeling and recovery status were determined by ST segment monitoring. The myocardial infarction area was observed by 2,3,5-triphenyltetrazolium chloride ( TTC) staining, and pathological inflammatory changes in the ischemic area of the mouse heart were observed by hematoxylin / eosin (HE) and Masson staining. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, serum creatine kinase isoenzyme ( CK-MB) levels were determined by enzyme-linked immunosorbent assay, and serum levels of lactate dehydrogenase (LDH), superoxide dismutase ( SOD) activity, and malondialdehyde (MDA) were detected using appropriate kits. The effects of the three medicines on the viability of human myocardial cells (AC16) after oxygen-glucose deprivation / reperfusion (OGD/ R) were compared by cell proliferation and cytotoxicity ( Cell Counting Kit-8) assays in vitro. Results Electrocardiogram examination revealed that the average heart rate was higher during reperfusion than during ischemia, indicating MIRI. The myocardial infarction area was reduced in the ZD-3, DG-3, and ZD-5 groups compared with the model group, as shown by TTC staining (P<0. 05), and HE and Masson staining indicated that the three drugs reduced the recruitment of inflammatory cells to varying degrees and inhibited myocardial tissue fibrosis (P<0. 05). Apoptosis and serum CK-MB levels were significantly reduced in the ZD-3 group ( P<0. 001, P < 0. 01, respectively). Detection of the myocardial enzyme LDH and oxidative stress indicators SOD and MDA 24 hours and 7 days after MIRI showed that ZD-3, DG-3, and ZD-5 reduced LDH activity,while ZD-3 and DG-3 also reduced the production of oxidative stress factors (P< 0. 01). ZD-3 also increased the survival of AC16 cells after OGD/ R in vitro (P<0. 05). Conclusions The Mongolian medicines DG-3, ZD-3, and ZD-5 can protect against MIRI in mice, with ZD-3 showing the best cardioprotective effect. Their mechanism involves reducing the infiltration of inflammatory cells and inhibiting cardiac tissue fibrosis. These preliminary result suggest that, under these experimental conditions, ZD-3 is a promising drug that can effectively inhibit the effects of MIRI.