Antifungal medications are vital in combatting fungal diseases that affect over a billion people annually. Antifungal medications for people and equids are scarce in Ethiopia, where lack of resources to treat fungal infection, in particular histoplasmosis, is a major health challenge. Histoplasmosis is endemic within the equine population in Ethiopia, where it is estimated that one in five horses are infected. This disease has far reaching impacts on equine welfare and the socio-economic wellbeing of families. The burden of histoplasmosis in people in Ethiopia is currently unknown, representing a blind spot in public health surveillance. Previous research has identified contact with wildlife, and domestic animal species as possible transmission pathways for histoplasmosis however, questions remain about the role of equids in human histoplasmosis. Given the close proximity of people and animals in this setting, the high level of endemic disease among equids, and the common sources of anti-fungals in Ethiopia, our study adopted a One-Health approach to examine how systemic issues affect access to, and use of antifungals to treat histoplasmosis among people and equids. A qualitative study was conducted in 6 urban regions of Oromia, Ethiopia in December 2018, incorporating semi-structured face-to-face interviews and focus group discussions. Twenty-seven individual interviews were held with doctors (n = 7), pharmacists (n = 12), veterinarians (n = 5), para-veterinarians (n = 2) and an equid owner (n = 1). Eleven focus groups were conducted with equid owners (n = 42), 3 with veterinarians (n = 6), 1 with para-veterinarians (n = 2) and 1 with pharmacists (n = 2). Transcripts were analysed using thematic analysis, and dimensions of key themes conceptualised and compared. Two overarching themes namely, ‘Structural’, and ‘Human factors’, summarised the main limitations to access to antifungal medications. ‘Structural factors’ included the national reliance on importation of medicines or pharmaceutical ingredients, inaccurate demand forecasting due to poor recording of the shortfall within the pharmaceutical supply chain, deficiencies in diagnostic capacity for fungal disease and, a healthcare system funded with a significant component of out-of-pocket expenditure. ‘Human factors’ that influenced access to antifungals included the perception of the expense of antifungals compared with competing needs such as food and education, the social stigma attached to histoplasmosis that could lead to delays in treatment seeking and, readily available home remedies or alternative treatment options. Furthermore, it was reported that trust in healthcare and veterinary provisions was undermined by a perceived lack of efficacious medications. Access to antifungals remains an urgent public health and animal welfare concern in Ethiopia. Key points within the supply and distribution chain that affect access to anti-fungals are identified, and policies that facilitate anti-fungal procurement and distribution should be reviewed. This paper highlights the structural, socio-economic and cultural factors influencing the management of infection with histoplasmosis, including how it is understood, identified and treated. This study identifies areas where further cross-sectorial work is needed to address these factors to improve disease control and clinical outcomes observed in human and animal histoplasmosis within Ethiopia.