Patients with Coronavirus disease 2019 (COVID-19) often have elevations in markers of liver injury, particularly serum aspartate transaminase (AST) and alanine transaminase (ALT). Such alterations may affect the AST/ALT ratio (De Ritis ratio) and, potentially, clinical outcomes. We conducted an updated systematic review and meta-analysis of the association between the De Ritis ratio and COVID-19 severity and mortality in hospitalized patients. PubMed, Web of Science, and Scopus were searched between 1 December 2019 and 15 February 2023. The Joanna Briggs Institute Critical Appraisal Checklist and the Grading of Recommendations, Assessment, Development, and Evaluation were used to assess the risk of bias and the certainty of the evidence, respectively. Twenty-four studies were identified. The De Ritis ratio on admission was significantly higher in patients with severe disease and non-survivors vs. patients with non-severe disease and survivors (15 studies, weighted mean difference = 0.36, 95% CI 0.24 to 0.49,p< 0.001). The De Ritis ratio was also associated with severe disease and/or mortality using odds ratios (1.83, 95% CI 1.40 to 2.39,p˂ 0.001; nine studies). Similar results were observed using hazard ratios (2.36, 95% CI 1.17 to 4.79,p= 0.017; five studies). In six studies, the pooled area under the receiver operating characteristic curve was 0.677 (95% CI 0.612 to 0.743). In our systematic review and meta-analysis, higher De Ritis ratios were significantly associated with severe disease and mortality in COVID-19 patients. Therefore, the De Ritis ratio can be useful for early risk stratification and management in this patient group (PROSPERO registration number: CRD42023406916).