Cryptococcal meningitis, caused by the fungal pathogen Cryptococcus neoformans, is a devastating disease with a mortality rate of over 80%. Due to the increasing prevalence of resistance to antifungals and the high mammalian toxicity of current treatments, the development of new antifungal therapies is vital. In an effort to improve the biological properties of a previously discovered antifungal peptoid, termed RMG8-8, an iterative structure–activity relationship study was conducted. This three-round study sought to optimize the structure of RMG8-8 by focusing on three main structural components: the lipophilic tail, aliphatic side chains, and aromatic side chains. In addition to antifungal testing against C. neoformans, cytotoxicity testing was also performed on all derivatives against human liver cells, and select promising compounds were tested for hemolytic activity against human red blood cells. A number of derivatives containing unique aliphatic or aromatic side chains had antifungal activity similar to RMG8-8 (MIC = 1.56 μg/mL), but all of these compounds were more toxic than RMG8-8. While no derivative was improved across all biological tests, modest improvements were made to the hemolytic activity with compound 9, containing isobutyl side chains in positions 2 and 5, compared to RMG8-8 (HC10 = 130 and 75 μg/mL, respectively). While this study did not yield a dramatically optimized RMG8-8 derivative, this result was not totally unexpected given the remarkable selectivity of this compound from discovery. Nonetheless, this study is an important step in the development of RMG8-8 as a viable antifungal therapeutic.