Pulmonary surfactant is a mixture of lipids and proteins, consisting of 90% phospholipid, and 10% protein by weight, found predominantly in pulmonary alveoli of vertebrate lungs. Two minor components of pulmonary surfactant phospholipids, phosphatidylglycerol (PG) and phosphatidylinositol (PI), are present within the alveoli at very high concentrations, and exert anti-inflammatory effects by regulating multiple Toll like receptors (TLR2/1, TLR4, and TLR2/6) by antagonizing cognate ligand-dependent activation. POPG also attenuates LPS-induced lung injury in vivo. In addition, these lipids bind directly to RSV and influenza A viruses (IAVs) and block interaction between host cells and virions, and thereby prevent viral replication in vitro. POPG and PI also inhibit RSV and IAV infection in vivo, in mice and ferrets. The lipids markedly inhibit SARS-CoV-2 infection in vitro. These findings suggest that both POPG and PI have strong potential to be applied as both prophylaxis and post-infection treatments for problematic respiratory viral infections.