BackgroundHigh-flow nasal cannula (HFNC) has been proven effective in improving patients with acute hypoxemic respiratory failure (AHRF), but a discussion of its use for initial flow settings still need to be provided. We aimed to compare the effectiveness and comfort evaluation of HFNC with different initial flow settings in patients with AHRF.MethodsStudies published by October 10, 2022, were searched exhaustively in PubMed, Embase, Web of Science, Cochrane Library (CENTRAL), and the China National Knowledge Infrastructure (CNKI) database. Network meta-analysis (NMA) was performed with STATA 17.0 and R software (version 4.2.1). A Bayesian framework was applied for this NMA. Comparisons of competing models based on the deviance information criterion (DIC) were used to select the best model for NMA. The primary outcome is the intubation at day 28. Secondary outcomes included short-term and long-term mortality, comfort score, length of ICU or hospital stay, and 24-h PaO2/FiO2.ResultsThis NMA included 23 randomized controlled trials (RCTs) with 5774 patients. With NIV as the control, the HFNC_high group was significantly associated with lower intubation rates (odds ratio [OR] 0.72 95% credible interval [CrI] 0.56 to 0.93; moderate quality evidence) and short-term mortality (OR 0.81 95% CrI 0.69 to 0.96; moderate quality evidence). Using HFNC_Moderate (Mod) group (mean difference [MD] − 1.98 95% CrI -3.98 to 0.01; very low quality evidence) as a comparator, the HFNC_Low group had a slight advantage in comfort scores but no statistically significant difference. Of all possible interventions, the HFNC_High group had the highest probability of being the best in reducing intubation rates (73.04%), short-term (82.74%) and long-term mortality (67.08%). While surface under the cumulative ranking curve value (SUCRA) indicated that the HFNC_Low group had the highest probability of being the best in terms of comfort scores.ConclusionsThe high initial flow settings (50–60 L/min) performed better in decreasing the occurrence of intubation and mortality, albeit with poor comfort scores. Treatment of HFNC for AHRF patients ought to be initiated from moderate flow rates (30–40 L/min), and individualized flow settings can make HFNC more sensible in clinical practice.Supplementary InformationThe online version contains supplementary material available at 10.1186/s40560-023-00667-2.