Histoplasmosis, a systemic mycosis caused by Histoplasma capsulatum, poses a fatal threat in endemic regions, yet remains rare in Vietnam and other regions in Asia due to ecological preferences for other fungi such as Talaromyces marneffei. This study aimed to characterize the epidemiological, clinical, and diagnostic aspects of histoplasmosis in Vietnam, compared with talaromycosis. Histoplasmosis presents a varied clinical spectrum that affects multiple organ systems ranging from mild to fatal cases. The clinical, laboratory, and radiologic similarities between histoplasmosis and talaromycosis complicate the clinical diagnosis. Distinct features in microscopy and culture can aid fungal differentiation. This study highlights the diagnostic challenges of histoplasmosis, advocating for the integration of epidemiological, clinical and laboratory data, suggesting advanced diagnostic methods using fungal antigen-based and molecular tests.