BackgroundA unified clinical definition of feeding intolerance (FI) is urged for better management of enteral nutrition (EN) in critically ill patients. We aimed to identify optimum clinical FI definitions based on reported evidence.MethodsWe searched clinical studies comparing FI with non-FI with a clear definition, summarized the evidence by random-effect meta-analyses, and rated the certainty of evidence by the Grading of Recommendations Assessment, Development and Evaluation frameworks.ResultsFive thousand five hundred twenty-five records were identified, of which 26 eligible studies enrolled 25,189 adult patients. Most patient-centered outcomes were associated with FI overall. Low to very low certainty evidence established FI defined as large gastric residual volume (GRV) ≥ 250 ± 50 mL combined with any other gastrointestinal symptoms (GIS) had a significant association with high mortalities in particular all-cause hospital mortality (odds ratio [OR] 1.90, 95% confidence interval [CI] 1.40–2.57), the incidence of pneumonia (OR 1.54, 95% CI 1.13–2.09) and prolonged length of hospital stay (mean difference 4.20, 95% CI 2.08–6.32), with a moderate hospital prevalence (41.49%, 95% CI 31.61–51.38%). 3-day enteral feeding (EF) delivered percentage < 80% had a moderate hospital prevalence (38.23%, 95% CI 24.88–51.58) but a marginally significant association with all-cause hospital mortality (OR 1.90, 95% CI 1.03–3.50).ConclusionsIn critically ill adult patients receiving EN, the large-GRV-centered GIS to define FI seemed to be superior to 3-day EF-insufficiency in terms of both close associations with all-cause hospital mortality and acceptable hospital prevalence (Registered PROSPERO: CRD42022326273).Trial registration: The protocol for this review and meta-analysis was registered with PROSPERO: CRD42022326273. Registered 10 May 2022.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40560-023-00674-3.