To explore the effect of D-β-hydroxybutyrate (DβHB) on acute myocardial infarction (AMI) in rats and its possible mechanism. Methods Forty SD rats were randomly divided into control group, myocardial infarction group, DβHB group and positive control group, with 10 rats in each group. Except for the control group, the remaining groups established AMI rat models by ligating the proximal end of the left anterior descending coronary artery. Rats in the DβHB groups were intraperitoneally injected with DβHB 100 mg/kg/d, rats in the positive control group were intraperitoneally injected with Betaloc 12 mg/kg/d, and rats in the control and myocardial infarction groups were injected with the same amount of normal saline for 3 weeks. Echocardiography was used to detect cardiac function; HE staining was used to detect cardiology changes; TTC staining was used to detect myocardial infarction area. ELISA kit was used to detect LDH and CK-MB activity. TUNEL staining was used to detect myocardial cell apoptosis. Western blot was used to detect apoptosis, Notch1/Hes1 pathway and endoplasmic reticulum stress related protein expression.Results Compared with the control group, the myocardial infarction group had disordered myocardial structure, obvious inflammatory cell infiltration and interstitial edema, cardiac function was significantly reduced, myocardial infarction area, LDH activity, CK-MB activity, myocardial cell apoptosis rate, Bax, p-PERK/PERK, p-eIF2α/eIF2α, ATF4 and CHOP protein expression were significantly increased (P＜0.05), Bcl-2 protein expression was significantly decreased (P＜0.05). The differences of Notch1, NICD and Hes1 protein expression were not statistical significance (P＞0.05）. Compared with the myocardial infarction group, the myocardial pathology changes in the DβHB group and positive control group were significantly improved, the cardiac function was significantly improved, myocardial infarction area, LDH activity, CK-MB activity, myocardial cells Apoptosis rate, Bax, p-PERK/PERK, p-eIF2α/eIF2α, ATF4 and CHOP protein expression were significantly reduced (P＜0.05), Bcl-2, Notch1, NICD and Hes1 protein expression were significantly increased (P＜0.05). Conclusion DβHB may improve acute myocardial infarction in rats by activating Notch1/Hes1 pathway and inhibiting endoplasmic reticulum stress.