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<i>Cryptococcus neoformans</i>, a life-threatening human yeast <i>pathogen,</i> has the ability to produce melanin, which is one of the common virulence factors contributing to cryptococcal pathogenesis. This virulence factor is closely associated with the cryptococcal cell wall, specifically chitin and chitosan polysaccharides, a complex structure that is essential for maintaining cellular structure and integrity. In this study, we aim to investigate the effects of two stingless bee (SLB) propolis from <i>Tetragonula laeviceps</i> and <i>Tetrigona melanoleuca</i> against cell wall-associated melanin in <i>C. neoformans,</i> and its immune response in RAW 264.7 macrophage. The ethanolic extract of SLB propolis (EEP) has strongly exhibited anti-cryptococcal activity. Moreover, EEP from both sources reduced chitin/chitosan and melanin production against <i>C. neoformans</i> in a dose-dependent manner. Likewise, the mRNA expression level of <i>CDA1, IPC1-PKC1</i> and <i>LAC1</i> genes involved in the cryptococcal melanization pathway was significantly decreased at 2 mg/mL in EEP treatment. Additionally, pretreatment with EEP prior to yeast infection dramatically reduced intracellular replication of <i>C. neoformans</i> in RAW 264.7 macrophages in a dose-dependent manner. This study might be a new insight to use a natural powerful source, not only acting to target cell wall-associated molecules, but also being capable to explore a novel strategy by which dysregulation of these molecules leads to promote immunomodulatory activity.