Objective To investigate 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, and to compare the efficacy of these three Mongolian medicines on MIRI. Methods Using 7-week-old male C57BL/6 mice, they were randomly divided into 6 groups: sham operation (Sham) group, model (Model) group, positive control group of Compound Danshen Dropping Pills (CDDP), Danggong-3 (DG-3) group, Zandan-3 (ZD-3) group, and Zadi-5 (ZD-5) group. The mice were administered drugs by gavage 14 days before the modeling. The reversible left anterior descending coronary artery ligation (LAD) method was used to establish the model, and the electrocardiogram ST segment of the mice was continuously monitored. The mice were sacrificed 24 hours or 7 days after reperfusion. The MIRI modeling and recovery status were determined by monitoring the ST segment of the electrocardiogram; TTC staining was used to observe the myocardial infarction area; hematoxylin-eosin (HE) staining and Masson staining were used to observe the pathological inflammatory changes in the ischemic area of the mouse heart; TUNEL cell apoptosis staining was used to determine the apoptosis of tissue cells; enzyme-linked immunosorbent assay (ELISA) was used to detect the level of mouse creatine kinase isoenzyme (CK-MB) in the serum; the activity detection kit was used to detect the lactate dehydrogenase (LDH), superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in the serum; in vitro cell experiments, the effects of three Tibetan medicines on the cell viability of human myocardial cells (AC16) after oxygen-glucose deprivation/reperfusion (OGD/R) treatment were compared by cell proliferation and cytotoxicity (CCK-8). Results Electrocardiogram (ECG) examination revealed that the average heart rate during reperfusion was higher than that during ischemia, indicating myocardial ischemia-reperfusion injury. Compared with the model group, the TTC staining results of the ZD-3, DG-3, and ZD-5 groups showed that the myocardial infarction area in mice was reduced (P < 0.05); HE and Masson staining results indicated that after administration of Tibetan medicine, the recruitment of inflammatory cells was reduced to varying degrees and the production of myocardial tissue fibrosis was inhibited (P < 0.05); in the TUNEL apoptosis detection, the apoptosis in the ZD-3 group was significantly reduced (P < 0.001); the CK-MB level in the serum of the ZD-3 group was significantly lower (P < 0.01); in addition, the detection of myocardial enzymes and oxidative stress indicators LDH, SOD, and MDA 24 hours and 7 days after MIRI showed that before and after modeling, administration of ZD-3, DG-3, and ZD-5 could reduce the LDH activity of myocardial enzymes, and the ZD-3 and DG-3 groups could reduce the production of oxidative stress factors (P < 0.01); finally, the in vitro experiment detected cell activity, and the ZD-3 group could increase the cell survival rate of AC16 cells after OGD/R (P < 0.05). Conclusions The Mongolian medicines DG-3, ZD-3 and ZD-5 all have protective effects on MIRI in mice. Among them, ZD-3 has a better protective effect on the heart. The mechanism is closely related to reducing the infiltration of inflammatory cells and inhibiting the formation of cardiac tissue fibrosis. Under these experimental conditions, it is preliminarily believed that Zandan-3 is a therapeutic heart medicine that can effectively inhibit MIRI.