Rising antifungal resistance prompted the World Health Organization and the Food and Agriculture Organization to bring attention to the consequences of this threat to human, animal, and environmental health, and food security. In addition, there is an alarming cross-species pathogenicity. New antifungal agents are urgently needed, preferably with a low induction of antimicrobial resistance (AMR). Among the most promising novel antimicrobials are the host-defense peptides, which present potent anti-infective properties and elicit low or negligible AMR. The rapid creation of libraries of host-defense peptides is highlighted by the synthesis of analogs of the immunomodulator and antimicrobial peptide rigin. Starting from smaller fragments incorporating hydroxyproline customizable units, which can be selectively cleaved and modified to give different lateral chains and N-substituents, two fragment libraries were built. Then the fragments were combined to give a library of rigin analogs, some of which displayed a potent antifungal activity not observed in the natural peptide. Surprisingly, the most active ones were N-substituted and lateral-chain protected analogs, while the free cationic peptides displayed low direct activity. This work shows that the strategy of combining site-selective peptide modification and a combinatorial approach can provide peptide-diverse libraries, where unexpected drug leads may be identified.