Background Histoplasmosis caused by Histoplasma capsulatum var. duboisii (Hcd) is a rare, but probably underestimated, endemic infection described in intertropical Africa. Therefore, the epidemiology of the infection remains unclear, and there is no consensus on therapeutic management. Methods Using a comprehensive search on different Internet databases, we collected case reports of Hcd infection published from 1993 to 2019. Epidemiological and clinical charts and therapeutic strategies were analyzed. Results We found 94 well-documented cases of Hcd infection, and 30.1% of the patients were under 18 years old. Symptoms occurred in some patients several decades after leaving the endemic area. Cutaneous/subcutaneous lesions, bone infections, and lymphadenopathies, both isolated and combined, were the most frequent presentations. The human immunodeficiency virus (HIV) coinfection rate was at 20.8%, with fever, lymphadenopathies, and an absence of bone infection being the differentiating elements from patients living without HIV. The rate of disseminated forms (60.6% in our review) significantly increased as compared to studies published before 1993, but without correlation with HIV infection. The global mortality rate was at 23.4% by the end of follow-up. The outcome was not correlated with the antifungal drug prescribed, nor with HIV serologic status, but was correlated with the initiation of an antifungal therapy. Conclusions Hcd histoplasmosis is a severe fungal infection for which the precise mode of acquisition remains to be determined. There is a need for affordable and more specific diagnostic tools. Itraconazole and amphotericin B are the best therapeutic alternatives and should be available in all low-income countries of the endemic area.