Enset (Ensete ventricosum) is a productive, drought-tolerant and multipurpose food security crop grown in the densely populated Ethiopian highlands. It is a so-called orphan crop, and its production suffers from a lack of information on proper soil fertility management and its interaction with bacterial wilt disease caused by the pathogen Xanthomonas campestris pv. musacearum. The aim of this study was therefore to assess soil-plant nutrient variation within enset home gardens at three altitudes (ranging from 2000 to 3000 m above sea level - a.s.l.) in the Gamo highlands and investigate whether this variation affects disease prevalence. Altitude in the rift valley covaries with soil leaching, and plant available P, Ca and Mg in soils significantly raised with decreasing altitude. Soil carbon and most nutrients reached very high levels in the gardens, whereas the more distant outfields were severely nutrient deprived. Differences in management intensity within the garden caused soil pH, conductivity, total organic carbon, total N and available P, K, Ca, Mg, Mn and Fe levels to significantly decline with distance from the house; yet, this decrease in soil nutrients was not mirrored in a response of foliar nutrient content, except for N. Hence, over-fertilization is likely, and establishing evidence-based nutrient recommendations for enset would benefit soil quality and productivity both in the gardens and in the outfields. Disease prevalence was high in the study area, with one-third of the farms affected in the recent past. Although more experimental work is needed to exclude confounding factors, our data indicate that the effects of altitude, P fertilization, micronutrients and K-Ca-Mg balance are promising avenues for further investigation into Xanthomonas wilt disease susceptibility.