Epizootic lymphangitis (EZL) is a chronic, contagious disease of equids caused by the fungus Histoplasma capsulatum var. farciminosum. The disease is often prevalent in cart pulling equids in developing countries. This study was undertaken in Central and South Gondar zones of Amhara region, Ethiopia with the objectives of estimating the prevalence of EZL in cart pulling horses and mules and identifying the risk factors of the disease. Two towns, one high altitude and one mid altitude, from each of the two zones were included for the study. A total of 528 cart pulling horses and mules from the selected towns were examined clinically, screened by physical examination based on clinical signs of the disease and confirmed by microscopic mycological examination of the causative agent. Potential risk factors data were collected through observation of cart animals and interviewing of cart owners and were statistically evaluated using mixed effect logistic regression. An overall EZL prevalence of 12.5% (95% CI: 9.9–15.6%) was found. The prevalence was 19.9% (95% CI: 15.8–24.8%) in horses and 5.8% (95% CI: 2.4–13.2%) in mules. The disease was prevalent in mid altitude towns but was not detected in high altitude cold towns of the study zones. The risk factor analysis revealed that sharing of harness, mingling of cart animals in cart stations, communal housing and pre-existing trauma wound were risk factors of EZL in cart pulling horses and mules. The study generally indicated that EZL is a prevalent problem in mid altitude towns that endangers the livelihood of the cart owners and wellbeing of cart pulling equids. This warrants the initiation of a control strategy mainly focusing on improving management of cart pulling equids related to the identified risk factors to ameliorate the EZL problem in the study area.