Cryptococcosis is a systemic mycosis caused by Cryptococcus neoformans and C. deuterogattii. Available therapeu-tic options are limited and face several challenges, including high toxicity, the emergence of resistant strains, high costs, and restrict-ed distribution. In this study, we evaluated the anticryptococcal potential of two compounds identified as antifungals from the Pan-demic Response Box, brilacidin (MMV1634402), a recently characterized fungicidal agent, and KIN1400 (MMV019724), an activa-tor of genes promoting antiviral responses. Both compounds exhibited inhibitory activity with minimum inhibitory concentrations (MICs) of 2.5 µM. Brilacidin demonstrated a high selectivity index (SI = 16) and low cytotoxicity in murine macrophages, whereas KIN1400 showed partial fungicidal activity and lower selectivity (SI = 2). Synergy assays revealed that brilacidin potentiated am-photericin B activity, reducing its effective dose up to eightfold without increasing cytotoxicity. Morphological analyses by scan-ning, confocal, and transmission electron microscopy confirmed previously described effects of brilacidin, in addition to profound alterations in capsule structure, plasma membrane integrity, and intracellular organization. KIN1400 induced milder, species-dependent effects, including a slight decrease in capsular size, discrete changes in cell wall organization, membrane pore formation, and intracellular alterations. These effects were more pronounced in C. neoformans than in C. deuterogattii. Brilacidin also inhibited C. neoformans biofilms, reducing metabolic activity and biomass in a concentration-dependent manner, accompanied by major structural disruption. Quantitative proteomics revealed that brilacidin and KIN1400 induced distinct, species-specific responses. Brilacidin primarily affected proteins involved in sterol metabolism, oxidative stress, and cell wall biosynthesis, while KIN1400 altered mitochondrial and RNA metabolic processes. These results provide translational knowledge for the future development of molecules with therapeutic potential against cryptococcosis.