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Background: Auranofin is an approved anti-rheumatic drug that has a broad-range inhibitory action against several microorganisms, including human pathogenic fungi. The auranofin activity against Histoplasma capsulatum, the dimorphic fungus that causes histoplasmosis, has not been properly addressed. Since there are few therapeutic options for this life-threatening systemic mycosis, this study evaluated the effects of auranofin on H. capsulatum growth and expression of virulence factors. Methodology/principal findings: Minimal inhibitory and fungicidal concentrations (MIC and MFC, respectively) of auranofin against 15 H. capsulatum strains with distinct genetic backgrounds were determined using the yeast form of the fungus and a microdilution protocol. Auranofin activity was also assessed on a macrophage model of infection and on a Tenebrio molitor invertebrate animal model. Expression of virulence-related genes was compared between auranofin treated and untreated H. capsulatum yeast cells using a quantitative PCR assay. Auranofin affected the growth of different strains of H. capsulatum, with MIC and MFC values ranging from 1.25 to 5.0 μM and from 2.5 to >10 μM, respectively. Auranofin was able to kill intracellular H. capsulatum yeast cells and conferred protection against the fungus in the experimental animal model of infection. Moreover, the expression of catalase A, HSP70, superoxide dismutase, thioredoxin reductase, serine proteinase, cytochrome C peroxidase, histone 2B, formamidase, metallopeptidase, Y20 and YPS3 proteins were reduced after six hours of auranofin treatment. CONCLUSIONS/SIGNIFICANCE: Auranofin is fungicidal against H. capsulatum and reduces the expression of several virulence-related genes, which makes this anti-rheumatic drug a good candidate for new medicines against histoplasmosis. Author summary: Histoplasmosis is a serious disease caused by the fungus Histoplasma capsulatum, which can be life-threatening and has limited treatment options. In this study, we investigated the potential of auranofin, a drug originally approved for treating rheumatoid arthritis, to combat H. capsulatum. We tested auranofin against different strains of the fungus and found that it effectively inhibited fungal growth. This drug was also effective in killing the fungus within cells from the immune system and provided protection in an experimental animal model. Furthermore, auranofin reduced the expression of several genes associated with the fungus's ability to cause disease. These genes are involved in critical functions such as detoxifying harmful substances and maintaining cellular structures. By suppressing these genes, auranofin hampers the fungus's ability to survive and cause infection. These findings suggest that auranofin could be repurposed as a treatment for histoplasmosis, offering a new avenue for therapy against this challenging infection. This research is significant because it highlights the potential of existing drugs to treat other diseases, broadening our arsenal of available treatments and contributing to better healthcare solutions. [ABSTRACT FROM AUTHOR]