Objective This study investigated the frequency and risk factors of acute liver injury (ALI) and the association between ALI and treatment in hospitalized patients with coronavirus disease 2019 (COVID-19). Methods This was a single-center retrospective study of 631 hospitalized patients ≥18 years old who were diagnosed with COVID-19 and received treatment between July 1, 2020, and January 31, 2024. Demographic and clinical data were extracted from the electronic medical records. ALI was defined according to the consensus guidelines of the Asia Pacific Association of the Study of Liver. Patients were divided into two groups according to the presence of ALI to assess the risk factors for the occurrence of ALI. Results Seventy-six patients (12.0%) developed ALI. Seven patients discontinued remdesivir owing to hepatic impairment, and only 1 patient (0.2%) had an increase in alanine aminotransferase (ALT) ≥10 times the upper limit of normal. ALI was associated with men (odds ratio [OR]=3.052, 95% confidence interval [CI]=1.456-6.398), a higher WHO ordinal scale score at admission (OR=1.408, 95% CI=1.036-1.912), higher ALT level at admission (OR=1.017, 95% CI=1.009-1.024), tocilizumab administration (OR=2.788, 95% CI=1.372-5.666), the absence of diabetes (OR=0.456, 95% CI=0.226-0.922) and the absence of dyslipidemia (OR=0.244, 95% CI=0.083-0.723). In the comparison of the propensity score-matched groups, neither remdesivir nor tocilizumab administration was associated with ALI. Conclusion Men, severe COVID-19, and elevated ALT levels at admission were significantly associated with an increased risk of ALI in patients treated for COVID-19. ALI may have been associated with tocilizumab administration but not with remdesivir administration.