Introduction: COVID-19 is a disease characterized by high in-hospital mortality, which seems to be dependent on many predisposing factors. Objectives: The aim of this study was to analyze the clinical symptoms, abnormalities in the results of laboratory tests, and coexisting chronic diseases that independently affected the risk of in-hospital mortality in patients with COVID-19. Patients and Methods: We analyzed the records of patients with COVID-19 who were hospitalized from 6 March 2020 to 30 November 2021. Results: Out of the entire group of 2138 patients who were analyzed, 12.82% died during hospitalization. In-hospital mortality was independently associated with older age (OR 1.53, 95% CI 1.20–1.97); lower arterial blood oxygen saturation (OR 0.95, 95% CI 0.92–0.99); the presence of a neoplasm (OR 4.45, 95% CI 2.01–9.62), a stomach ulcer (OR 3.35, 95% CI 0.94–11.31), and dementia (OR 3.40, 95% CI 1.36–8.26); a higher score on the SOFA scale (OR 1.73, 95% CI 1.52–1.99); higher lactate dehydrogenase (LDH) (OR 1.08, 95% CI 1.05–1.12); higher N-terminal pro-brain natriuretic peptide (NT pro BNP) (OR 1.06, 95% CI 1.01–1.11); and lower total bilirubin in blood concentration (OR 0.94, 95% CI 0.90–0.99). Conclusions: We found that low oxygen saturation, old age, and the coexistence of cancer, gastric ulcers, and dementia syndrome were variables that independently increased mortality during hospitalization due to COVID-19. Moreover, we found that decreased platelet count and bilirubin concentration and increased levels of LDH and NT-proBNP were laboratory test results that independently indicated a higher risk of mortality. We also confirmed the usefulness of the SOFA scale in predicting treatment results. The ability to identify mortality risk factors on admission to hospital will facilitate both adjusting the intensity of treatment and the monitoring of patients infected with SARS-CoV-2.