Background: Around 80% of the people of Ethiopia are estimated to be relying on medicinal plants for the treatment of different types of human health problems. The purpose of this study was to describe and analyse the use and management of medicinal plants used for the treatment of human health problems by the Maale and Ari communities in southern Ethiopia.Methods: Quantitative and qualitative ethnobotanical field inquiries and analytical methods including individual and focus group discussions (18), observations, individual interviews (n = 74), preference ranking and paired comparison were used. Data were collected in three study sites and from two markets; the latter surveyed every 15 days from February 2011 to February 2012.Results: A total of 128 medicinal plant species, belonging to 111 genera and 49 families, used as herbal medicine by Maale and Ari communities were documented. Predominantly harvested plant parts were leaves, which are known to have relatively low impact on medicinal plant resources. Species with high familiarity indices included Solanum dasyphyllum, Indigofera spicata, Ruta chalepensis, Plumbago zeylanica and Meyna tetraphylla. Low Jaccards similarity indices (≤ 0.33) indicated little correspondence in medicinal plant use among sites and between ethnic communities. The dominant ways of medicinal plant knowledge acquisition and transfer is vertical: from parents to children through oral means. Gender and site significantly influenced the number of human medicinal plants known currently in the study sites. Age was only a factor of significance in Maale. Marketing of medicinal plants harvested from wild and semi-wild stands is not common. Expansion of agricultural land and lack of cultivation efforts by local communities are mentioned by locals to affect the availability of medicinal plant resources.Conclusion: S. dasyphyllum, I. spicata, P. zeylanica, M. tetraphylla, and Oxalis radicosa need to be considered for phytochemical and pharmacological testing to verify their efficacy and determine their dosages. Land use planning and development initiatives in the area and beyond need to sharply focus on strategies that could alleviate the major threats affecting medicinal plant resources in the landscape and encourage their cultivation to enhance their availability and complement ex-and in-situ conservation.