Cardiogenic shock is associated with a high mortality rate in patients with acute myocardial infarction (AMI). We developed a new treatment approach named heart rest therapy (HRT) for complete revascularization in the early stage of AMI using an ultra-short-acting β-blocker (landiolol) and an Impella(®) left ventricular assist device and verified the effect of this therapy in a swine model. In 18 male pigs, AMI was induced by left anterior descending coronary artery occlusion at the level of the second diagonal branch for 120 min, followed by 240 min of reperfusion. The animals were divided into three groups: group A had no support, group B was supported with the Impella(®), and group C was treated with HRT from 90 min after ischemia to 240 min after reperfusion. Infarct ratio (percentage of the infarct area relative to the area at infarct risk) was significantly reduced in group C (group A 65.38 ± 6.07, group B 39.66 ± 11.16, group C 21.78 ± 7.29), with a significant difference between groups A and B (P < 0.001), A and C (P < 0.001), and B and C (P = 0.006). Heart rates were significantly lower in group C at 30 min (P = 0.01), 60 min (P = 0.022), and 240 min (P = 0.032) after reperfusion compared with group B, without development of hypotension. HRT at the early stage in AMI stabilized the hemodynamic conditions and reduced infarct size and complications in a swine model. These results suggest that HRT can improve the prognosis of patients with AMI.