The biological and immune-protective properties of surfactant-derived phospholipids and phospholipid-subfractions in the context of neonatal inflammatory lung disease are widely unknown. Using a porcine neonatal triple-hit ARDS model (repeated airway lavage, overventilation, LPS instillation into airways), we assessed whether the supplementation of surfactant (poractant alfa, S) with inositol-derivatives (inositol-1,2,6-trisphosphate, IP3; phosphatidylinositol-3,5-bisphosphate, PIP2) or phosphatidylglycerol-subfractions (16:0/18:1-POPG; 18:1/18:1-DOPG) would result in improved clinical parameters, and sought to characterize changes in key inflammatory pathways behind these improvements. Within 72 h of mechanical ventilation, the oxygenation index (S+IP3/PIP2/POPG), the ventilation efficiency index (S+IP3/POPG), the compliance (S+IP3/POPG) and the resistance (S+POPG) of the respiratory system, and the extra-vascular lung water index (S+IP3/POPG) significantly improved compared to S treatment alone. The inositol-derivatives (mainly S+IP3) exerted their actions by suppressing the acid sphingomyelinase activity and dependent ceramide production, linked with the suppression of the inflammasome NLRP3/ASC/caspase-1 complex, and the pro-fibrotic response represented by the cytokines TGF-β1 and IFN-, matrix metalloproteinase (MMP)-1/8, and elastin. In addition, IB-kinase activity was significantly reduced. S+POPG/DOPG treatment inhibited polymorpho-nuclear leukocyte activity (MMP-8, myeloperoxidase), the production of interleukin-6, maintained alveolar-capillary barrier functions, and reduced alveolar epithelial cell apoptosis all of which resulted in reduced pulmonary edema. S+DOPG also limited the profibrotic response. We conclude that highly concentrated inositol-derivatives and phosphatidylglycerol-subfractions in surfactant preparations mitigate key inflammatory pathways in inflammatory lung disease, and that their clinical application may be of interest for future treatment of the acute exudative phase of neonatal ARDS.