Induction of myocardial infarction (MI) in mice is typically performed by surgical ligation of a coronary artery, a low-throughput procedure with high method-associated variability. We sought to establish a minimal-invasive, highly reproducible approach to induce MI in mice. After visualization of the coronary arteries with high-resolution ultrasound imaging, the target segment of the left anterior descending artery (LAD) was occluded with a micromanipulator-controlled monopolar needle by the use of high-frequency electricity. After the intervention, successful MI could be directly validated by a) absence of blood flow distal of occlusion, b) akinesia in the affected part of the left ventricle, and c) typical ECG changes (ST elevation) within seconds after LAD occlusion (procedure time 6.2 ± 1.8 minutes). Serum cTnT levels were markedly increased at day 1 and 3 after the intervention compared to baseline accompanied by significantly reduced cardiac systolic function in the follow-up. Furthermore, the approach enabled induction of standardized and pre-defined MI sizes based on LAD length and diagonal branching and delivered significant animal welfare benefits (no ventilation / no thoracotomy). The technique allows real-time assessment of cardiac function, control of infarction size and thereby additional stratification directly after the procedure, which might be particularly useful for studies investigating novel therapeutic or interventional strategies in mice after MI.