Background:  Most of the study reviews on Histoplasma capsulatum var duboisii (Hcd) infection have been limited to case reports from few African countries despite having cases reported outside Africa. We aimed at providing an update on the global epidemiology of histoplasmosis caused by Hcd, its diagnostic challenges and recommendations for improved diagnosis. Materials and methods: We conducted a retrospective review of case reports and case series on Hcd infection published “between 1^st January 1950 to 31^st December 2021" using PubMed, Google Scholar and African Journals Online. The following search terms: “African histoplasmosis" and “Histoplasma duboisii" AND/OR “diagnosis of African histoplasmosis" were used. Publications on histoplasmosis caused byH. capsulatum var. capsulatum (Hcc) were excluded. Data extracted from each case included: age, gender, disease type (single organ vs. disseminated disease), sites of infection, clinical features, HIV status, diagnostic tests, treatment, and patient outcome. Results: We identified 415 cases of Hcd infection reported globally (1950 – 2021); 359 (86.5%) cases from Africa, while 56 (13.5%) were from other geographical regions, Hcd infection was misdiagnosed as other clinical entities including tuberculosis, malignancies, osteomyelitis, neurofibromatosis, and cystic lesions. Out of the 415 cases, diagnostic modality was specified in 307 (74%) cases, with histopathology (n=270, 87.9%) as the predominant diagnostic method followed by culture (n=59, 19.2%). Conclusion: Like classical histoplasmosis, the clinical presentation of Hcd infection mimics other diseases, hence a high index of suspicion by the attending clinician would be invaluable in making a prompt diagnosis and invariably improve clinical outcomes. In addition, there is a need to build capacity in molecular diagnostics and antigen assay specific for detecting Hcdinfection as classical diagnostic methods have been proven to be inadequate.