The transition from the sterile maternal womb to microbe-rich extrauterine environments presents immunological challenges to mammalian newborns. Born with underdeveloped immune tissues, marsupial neonates require specialized immunological protections from microbial pathogens. However, exact identity and the composition of the protective immune cells and compounds expressed by marsupial neonates remain unknown. Here, combining transcriptomic, epigenomic, functional assays, and comparative genomics, we have investigated immunological defense strategies of marsupial neonates using the sugar glider (Petaurus breviceps) as a model. We have identified neutrophils and cathelicidin genes as a key cell type and key genes in marsupial newborns. Further transcriptomic and proteomic analyses have detected the expression of cathelicidins in multiple hematopoietic tissues as well as in the maternal milk. Through syntenic analyses, we discovered that sugar glider cathelicidin genes reside in two genomic clusters and that marsupials and monotremes are the only tetrapods that retained two cathelicidin gene clusters while eutherians and non-mammalian tetrapods possess only one cluster. Subsequent epigenomic analyses have shown that the coordinated expression of cathelicidin genes across two clusters is achieved by enhancer sharing within clusters and longrange physical interactions between clusters. Finally, in vitro and in vivo immunological asssays have discovered the direct antimicrobial activity as well as the immunomodulatory properties of multiple cathelicidin genes. By wholistically characterizing the evolution, regulation, and function of the cathelicidin gene family, our results identified the key mediator of the marsupial neonatal immune protection.