Lockdown and re-opening may become cyclical due to the recurrent waves of the COVID-19 epidemic. Few studies have examined temporal trends and determinants of in-hospital mortality among patients with ST-segment elevation myocardial infarction (STEMI), a life-threatening condition that requires emergency medical care. Using nation-wide data before, during and after the Wuhan lockdown, we aimed to depict temporal patterns and major determinants of STEMI in-hospital mortality in China across five time periods of the COVID-19 epidemic. We analyzed the data of 283,661 STEMI patients who were admitted to 4,487 chest-pain-centers across China, from January 1, 2019 to May 31, 2020. Compared with the period before the lockdown, STEMI in-hospital mortality increased by 25% (OR 1.25, 95%CI 1.16–1.34) during Early Lockdown, by 12% (OR 1.12, 95%CI 1.03–1.22) during Later Lockdown, by 35% (OR 1.35, 95%CI 1.21–1.50) during Early Lift, and returned to pre-COVID risk (OR 1.04, 95%CI 0.95–1.14) during Later Lift. For each time-period, we observed a clear mortality gradient by timing and types of revascularization procedure. In conclusion, the COVID-19 epidemic had a significant adverse impact on STEMI in-hospital mortality, with bimodal peaks during early lockdown and early lift periods and clear mortality gradients by timing and types of revascularization procedure, independent of the time periods.Supporting InformationThe supporting information is available online at 10.1007/s11427-021-2046-4. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.