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Background: To combat infection, an immune system needs to be promptly activated but tightly controlled to avoid destruction of host tissues. IbinA and IbinB are related short peptides with robust expression upon microbial challenge in Drosophila melanogaster. Results: Ibin genes are ubiquitously present in flies of the Drosophila subgenus Sophophora, replacing the likely evolutionarily older, related gene, Mibin, which is found across a much wider range of cyclorrhaphan flies and is also upregulated following infection. We observed no direct bactericidal or bacteriostatic activity for IbinA or IbinB in vitro. Using single and double Ibin mutant Drosophila lines, we examined their roles in development and during microbial infections. IbinA is expressed in early pupae, and a lack of IbinA and IbinB leads to temperature-dependent formation of melanized tissue during metamorphosis, frequently around the trachea. IbinA and IbinB have distinct effects on susceptibility to microbial infection. For example, flies lacking IbinB had improved survival when challenged with Listeria monocytogenes, an intracellular pathogen, whereas a lack of IbinA alone had no effect. RNA sequencing following L. monocytogenes infection showed enhanced Toll target gene expression in flies lacking IbinB, suggesting that IbinB acts as a negative regulator of the Toll pathway. In contrast, IbinA mutants had decreased Toll target gene expression. Correspondingly, IbinB mutant flies had improved, and IbinA compromised survival in septic fungal infection, where the Toll pathway has a major role. Conclusions: Our study provides insight into the roles of IbinA and IbinB in regulation of the immune response in Drosophila.