Aseko district, part of the Hararghe and Arsi Bale massivemountainous region in southeast Ethiopia, is renowned for its religious culture and traditions. The local People believe that plants are sacred to God and hold medicinal potential. This study aims to investigate ethnomedicinal knowledge of plants used to treat human ailments in the district. Ethnobotanical data were collected through semi-structured interviews, key informants' interviews, guided field observations, and focus group discussions. Quantitative methods wereemployed to calculate the Informant Consensus Factor (ICF), preference ranking, and Fidelity level values. The finding revealed that 96 species (trees 24%; shrubs 28%; herbs 40%) belonging to 89 genera and 66 families are utilized as medicinal plants to treat human ailments by indigenous people and local communities of the district. The plant Families with the highest number of species were Lamiaceae and Solanaceae, followed by Fabaceae. It was foundthat leaves (44%), roots (19%), and barks (10%) of species of these species are commonly used,raising concerns that such extensive use may significantly reduce their populations. Therefore, there is an urgent need for aproper conservation plan and management strategy for medicinal plants.