Ischaemic heart disease remains a leading cause of premature mortality and morbidity. Understanding the associated pathophysiological mechanisms of cardiac dysfunction arising from ischaemic heart disease and the identification of sites for new therapeutic interventions requires a preclinical model that reproduces the key clinical characteristics of myocardial ischaemia, reperfusion and infarction. Here, we describe and validate a refined and minimally invasive translationally relevant approach to induce ischaemia, reperfusion and infarction in the sheep. The novelty and refinement in the procedure stems from utilization of implantable cardiac defibrillators prior to coronary engagement, balloon angioplasty to induce infarction, and intra-operative anti-arrhythmic drug protocols to reduce adverse arrhythmic events. The protocol is readily adoptable by researchers with access to standard fluoroscopic instrumentation, and it requires minimally invasive surgery. These refinements lead to a substantial reduction of intra-operative mortality to 6.7% from previously published values ranging between 13% and 43%. The model produces key characteristics associated with the fourth universal definition of myocardial infarction, including ECG changes, elevated cardiac biomarkers and cardiac wall motility defects. In conclusion, the model closely replicates the clinical paradigm of myocardial ischaemia, reperfusion and infarction in a translationally relevant large animal setting, and the applied refinements reduce the incidence of intra-operative mortality typically associated with preclinical myocardial infarction models.