To evaluate the efficacy and safety of fibrinolysis strategy in patients with acute ST-segment elevation myocardial infarction (STEMI) during the COVID-19 epidemic, and to provide reference value for optimization of fibrinolytic process on the premise of prevention and control of COVID-19 transmission, including self-protection of medical staff. The efficacy and safety of fibrinolysis were retrospectively analyzed in 7 patients with acute STEM, who hospitalized from February 29, 2020 to April 3, 2020 in the Department of Cardiology, Wuhan Union Hospital of Tongji Medical College, Huazhong University of Science and Technology. To optimize the fibrinolytic process on the premise of prevention and control of COVID-19 transmission, including self-protection of medical staff, a full-time medical team in charge of fibrinolysis under third-grade protection was established. The acute STEMI patients were treated immediately in a fixed and isolated area in emergency department before receiving green channel fibrinolysis. Blood samples for complete blood count, COVID-19 antibody test and nasopharyngeal swab samples for COVID-19 nucleic acid test were made before fibrinolysis, while the chest CT examination was accomplished after fibrinolysis. By comparing differences of time from the first electrocardiogram (ECG) to fibrinolysis before and after the improvement of fibrinolytic process, the effect of optimization of the fibrinolytic process was evaluated. In the present study, seven patients with acute STEMI received fibrinolysis therapy, 6 of them achieved reperfusion and no bleeding was observed in all of the patients. Five out of the 7 patients were hospitalized after fibrinolysis, and the hospitalization days were 19.6 days on average. By following up to April 14, 2020, none of the 7 patients died. The first 2 patients were treated according to the routine medical procedure and the time from the first ECG to fibrinolysis were 201 and 106 minutes, respectively. After the optimization of the fibrinolytic process, the time from the first ECG to fibrinolysis of the last 5 patients were 42, 46, 51, 43 and 54 minutes, respectively，which was significantly shorter than that before optimization. During the COVID-19 epidemic, fibrinolysis in patients with acute STEMI is safe, effective and easy to implement. Therefore, it is recommended as the top priority for the patients with acute STEMI with indications for fibrinolysis. On the premise of prevention and control of COVID-19 transmission, including self-protection of medical staff, the duration of myocardial ischemia can be shortened by optimization of the fibrinolytic process.