Background: The COVID-19 pandemic increased the complexity of the clinical management and pharmacological treatment of patients presenting with an Acute Coronary Syndrome (ACS). Aim: to explore the incidence and prognostic impact of in-hospital bleeding in patients presenting with ACS before and during the COVID-19 pandemic. Methods: We evaluated in-hospital Thrombolysis In Myocardial Infarction (TIMI) major and minor bleeding among 2851 patients with ACS from 17 Italian centers during the first wave of the COVID-19 pandemic (i.e., March–April 2020) and in the same period in the previous two years. Results: The incidence of in-hospital TIMI major and minor bleeding was similar before and during the COVID-19 pandemic. TIMI major or minor bleeding was associated with a significant threefold increase in all-cause mortality, with a similar prognostic impact before and during the COVID-19 pandemic. Conclusions: the incidence and clinical impact of in-hospital bleeding in ACS patients was similar before and during the COVID-19 pandemic. We confirmed a significant and sizable negative prognostic impact of in-hospital bleeding in ACS patients.