Background: Acute myocardial infarction complicated by cardiogenic shock (AMI‐CS) is associated with significant morbidity and mortality. Mechanical circulatory support (MCS) devices increase systemic blood pressure and end organ perfusion while reducing cardiac filling pressures. Methods and Results: The National Cardiogenic Shock Initiative (NCT03677180) is a single‐arm, multicenter study. The purpose of this study was to assess the feasibility and effectiveness of utilizing early MCS with Impella in patients presenting with AMI‐CS. The primary end point was in‐hospital mortality. A total of 406 patients were enrolled at 80 sites between 2016 and 2020. Average age was 64±12 years, 24% were female, 17% had a witnessed out‐of‐hospital cardiac arrest, 27% had in‐hospital cardiac arrest, and 9% were under active cardiopulmonary resuscitation during MCS implantation. Patients presented with a mean systolic blood pressure of 77.2±19.2 mm Hg, 85% of patients were on vasopressors or inotropes, mean lactate was 4.8±3.9 mmol/L and cardiac power output was 0.67±0.29 watts. At 24 hours, mean systolic blood pressure improved to 103.9±17.8 mm Hg, lactate to 2.7±2.8 mmol/L, and cardiac power output to 1.0±1.3 watts. Procedural survival, survival to discharge, survival to 30 days, and survival to 1 year were 99%, 71%, 68%, and 53%, respectively. Conclusions: Early use of MCS in AMI‐CS is feasible across varying health care settings and resulted in improvements to early hemodynamics and perfusion. Survival rates to hospital discharge were high. Given the encouraging results from our analysis, randomized clinical trials are warranted to assess the role of utilizing early MCS, using a standardized, multidisciplinary approach.