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Multidrug-resistant <i>Cryptococcus neoformans</i> is an encapsulated yeast causing a high mortality rate in immunocompromised patients. Recently, the synthetic peptide <i>Mo</i>-CBP₃-PepII emerged as a potent anticryptococcal molecule with an MIC₅₀ at low concentration. Here, the mechanisms of action of <i>Mo</i>-CBP₃-PepII were deeply analyzed to provide new information about how it led <i>C. neoformans</i> cells to death. Light and fluorescence microscopies, analysis of enzymatic activities, and proteomic analysis were employed to understand the effect of <i>Mo</i>-CBP₃-PepII on <i>C. neoformans</i> cells. Light and fluorescence microscopies revealed <i>Mo</i>-CBP₃-PepII induced the accumulation of anion superoxide and hydrogen peroxide in <i>C. neoformans</i> cells, in addition to a reduction in the activity of superoxide dismutase (SOD), ascorbate peroxidase (APX), and catalase (CAT) in the cells treated with <i>Mo</i>-CBP₃-PepII. In the presence of ascorbic acid (AsA), no reactive oxygen species (ROS) were detected, and <i>Mo</i>-CBP₃-PepII lost the inhibitory activity against <i>C. neoformans</i>. However, <i>Mo</i>-CBP₃-PepII inhibited the activity of lactate dehydrogenase (LDH) ergosterol biosynthesis and induced the decoupling of cytochrome <i>c</i> (Cyt c) from the mitochondrial membrane. Proteomic analysis revealed a reduction in the abundance of proteins related to energetic metabolism, DNA and RNA metabolism, pathogenicity, protein metabolism, cytoskeleton, and cell wall organization and division. Our findings indicated that <i>Mo</i>-CBP₃-PepII might have multiple mechanisms of action against <i>C. neoformans</i> cells, mitigating the development of resistance and thus being a potent molecule to be employed in the production of new drugs against <i>C. neoformans</i> infections.