Thromboprophylaxis is a mainstay of treatment of hospitalized COVID-19 patients, due to the high occurrence of thrombotic events. This increases the risk of bleeding. However, data on bleeding events and associated risk factors are scarce. Thus, we aimed to investigate the incidence, predictors and clinical outcomes associated with major bleeding in hospitalized COVID-19 patients. We retrospectively evaluated a cohort of 4014 consecutively hospitalized COVID-19 patients treated in a tertiary-level institution in the period 3/2020–3/2021. Bleeding of any kind was documented in 322 (8%) and major bleeding in 129 (3.2%) patients. A total of 129 (40.1%) bleeding events were present at the time of hospital admission, and 193 (59.9%) occurred during hospitalization. In the multivariate logistic regression analysis, intensive-care-unit treatment (adjusted odds ratio (aOR) 6.55; p < 0.001), atrial fibrillation (aOR 2.55; p = 0.029), higher white-blood-cell count (WBC) (aOR 1.03; p = 0.021), lower hemoglobin (aOR 0.97; p = 0.002) and history of bleeding (aOR 17.39; p < 0.001) were recognized as mutually independent predictors of major bleeding. Major bleeding was significantly associated with increased in-hospital mortality compared to non-major-bleeding patients (59.7% vs. 34.8%, p < 0.001), especially if occurring during hospitalization. Median time from major bleeding to death was 5 days. Bleeding events are frequent in hospitalized COVID-19 patients, with a significant proportion of patients presenting at the time of hospital admission, and others almost universally exposed to anticoagulant and corticosteroid therapies. Major bleeding is associated with high mortality, especially if occurring during hospitalization. The recognition of patients at risk and implementation of timely interventions are of high clinical importance.