The absence or dysfunction of lung surfactant (LS) is causally related to many different disease states, including respiratory distress syndrome (RDS). While animal-derived surfactant replacement therapy (SRT) is effective in the treatment of neonatal RDS, its limitations include high cost, batch-to-batch variability, and potential for an immune sensitization of the recipient. We are developing synthetic mimics of lung surfactant proteins SP-B and SP-C based on oligo-N-substituted glycines, or “peptoids”, that demonstrate the potential to improve pulmonary biophysical functionality while circumventing the shortcomings of animal-derived therapy. Here we report that a formulation including mimics of both SP-B and SP-C can exhibit superior in vitro surface activity than either component alone. Additionally, in vitro biocompatibility screening of peptoids using NIH 3T3 and A549 lung epithelial cells shows that surface-active mimics can be significantly less toxic than their peptide mimic counterparts. We also demonstrate proof-of-concept efficacy of some of our most promising lung surfactant protein mimics using the rat washout model of RDS. Taken together, these results suggest that peptoid-based mimic formulations have the potential to be important therapeutic agents in the treatment of RDS.