ObjectiveTo describe the potential effects of ventilatory strategies on the outcome of acute brain-injured patients undergoing invasive mechanical ventilation.DesignSystematic review with an individual data meta-analysis.SettingObservational and interventional (before/after) studies published up to August 22nd, 2022, were considered for inclusion. We investigated the effects of low tidal volume Vt < 8 ml/Kg of IBW versus Vt >  = 8 ml/Kg of IBW, positive end-expiratory pressure (PEEP) < or >  = 5 cmH2O and protective ventilation (association of both) on relevant clinical outcomes.PopulationPatients with acute brain injury (trauma or haemorrhagic stroke) with invasive mechanical ventilation for ≥ 24 h.Main outcome measuresThe primary outcome was mortality at 28 days or in-hospital mortality. Secondary outcomes were the incidence of acute respiratory distress syndrome (ARDS), the duration of mechanical ventilation and the partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio.ResultsThe meta-analysis included eight studies with a total of 5639 patients. There was no difference in mortality between low and high tidal volume [Odds Ratio, OR 0.88 (95%Confidence Interval, CI 0.74 to 1.05),p= 0.16,I2= 20%], low and moderate to high PEEP [OR 0.8 (95% CI 0.59 to 1.07),p= 0.13,I2= 80%] or protective and non-protective ventilation [OR 1.03 (95% CI 0.93 to 1.15),p= 0.6,I2= 11]. Low tidal volume [OR 0.74 (95% CI 0.45 to 1.21,p= 0.23,I2= 88%], moderate PEEP [OR 0.98 (95% CI 0.76 to 1.26),p= 0.9,I2= 21%] or protective ventilation [OR 1.22 (95% CI 0.94 to 1.58),p= 0.13,I2= 22%] did not affect the incidence of acute respiratory distress syndrome. Protective ventilation improved the PaO2/FiO2ratio in the first five days of mechanical ventilation (p< 0.01).ConclusionsLow tidal volume, moderate to high PEEP, or protective ventilation were not associated with mortality and lower incidence of ARDS in patients with acute brain injury undergoing invasive mechanical ventilation. However, protective ventilation improved oxygenation and could be safely considered in this setting. The exact role of ventilatory management on the outcome of patients with a severe brain injury needs to be more accurately delineated.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13054-023-04509-3.