The role of awake prone positioning (aPP) in patients with acute hypoxemic respiratory failure is debated. We performed a systematic review and meta-analysis to evaluate the role of aPP in acute respiratory failure related to COronaVIrus Disease-19 (COVID-19). Studies reporting on the clinical course of patients with acute respiratory failure related to COVID-19 treated or not treated by aPP were included in the systematic review and meta-analysis (ProsperoID: CRD42022333211). The primary study outcome was the composite of in-hospital death or orotracheal intubation; the individual components of the primary outcome were secondary study outcomes. The composite of in-hospital death or orotracheal intubation was available for 6 studies (1884 patients), five randomized and one prospective; a significant reduction in the risk of this outcome was observed in patients treated vs. not treated by aPP (33.5% vs. 39.8%; OR 0.73, 95% CI 0.60–0.89; I2 0%). In-hospital death was reported in 34 studies (6808 patients) and occurred in 17.4% vs. 23.5% of patients treated or not treated with aPP (random effect OR 0.60, 95% CI 0.46–0.79; I2 59%); orotracheal intubation was observed in 25.8% vs. 32.7% of patients treated or not treated with aPP (27 studies, 5369 patients; random effect OR 0.85, 95% CI 0.56–1.27; I2 84%). aPP reduces the risk for death or orotracheal intubation in patients with acute respiratory failure related to COVID-19. Further studies should be conducted to confirm the clinical benefit of aPP outside the ICU.Registration Prospero ID: CRD42022333211.