Background: In the management of patients with ST-elevation myocardial infarction (STEMI), system delays for reperfusion therapy are still a matter of concern. We investigated the impact of prehospital activation of the catheterization laboratory in the management of STEMI patients. Methods and Results: This is a systematic review of observational studies. A search was conducted of the PubMed database from inception to July 2020 to identify articles for inclusion in the study. The critical outcomes were short- and long-term mortality. The important outcome was door-to-balloon time. The GRADE approach was used to assess the certainty of the evidence. Seven studies assessed short-term mortality; 1,541 were assigned to the prehospital activation (PH) group and 1,191 were assigned to the emergency department activation (ED) group. There were 26 fewer deaths per 1,000 patients in the PH group. Three studies assessed long-term mortality; 713 patients were assigned to the PH group and 1,026 were assigned to the ED group. There were 54 fewer deaths per 1,000 patients among the PH group. Five studies assessed door-to-balloon time; 959 were assigned to the PH group and 631 to the ED group. Door-to-balloon time was 33.1 min shorter in the PH group. Conclusions: Prehospital activation of the catheterization laboratory resulted in lower mortality and shorter door-to-balloon time for patients with suspected STEMI outside of a hospital.