BACKGROUND: Despite advances in metabolomic research on COVID-19, existing studies have small sample sizes and few have comprehensively described the metabolic characteristics of patients with COVID-19 at each stage. In this systematic review, we aimed to summarise the similarities and differences of biomarkers in patients with COVID-19 of different severity and describe their metabolic characteristics at different stages. METHODS: We retrieved studies from PubMed, Embase, Web of Science, and the Cochrane Library published by October 2022. We performed a meta-analysis on untargeted and targeted metabolomics research data, using the ratio of means as the effect size. We compared changes in metabolite levels between patients with varying severity and controls and investigated sources of heterogeneity through subgroup analyses and meta-regression analysis. RESULTS: We included 22 cohorts from 21 studies, comprising 2421 participants, including COVID-19 patients of varying severity and healthy controls. We conducted meta-analysis and heterogeneity analysis on the 1058 metabolites included in the study. The results indicated that, compared to the healthy control group, 23 biomarkers were associated with mild cases (P <
0.05), 3 biomarkers with moderate cases (P <
0.05), and 37 biomarkers with severe cases (P <
0.05). Pathway enrichment analysis revealed significant disturbances in amino acid metabolism, aminoacyl-tRNA biosynthesis, primary bile acid biosynthesis, pantothenate and CoA biosynthesis, the tricarboxylic acid cycle, taurine and hypotaurine metabolism, and nitrogen metabolism in patients with mild, moderate, and severe disease. Additionally, we found that each severity stage exhibited unique metabolic patterns (all P <
0.05) and that the degree of metabolic dysregulation progressively worsened with increasing disease severity (P <
0.05). CONCLUSIONS: The results of our meta-analysis indicate the similarities and differences of biomarkers and metabolic characteristics of patients with different severity in COVID-19, thereby providing new pathways for the study of pathogenesis, the development precise treatment, and the formulation of comprehensive strategies. REGISTRATION: PROSPERO: CRD42022369937.