Indigenous people have developed their own knowledge on plant use and conservation for many years. This ethnobothanical study was carried out to investigate and document the use of medicinal plants in Sedie Muja woreda. In this study, 16 purposively selected key informants and 72 randomly selected informants from 5 sampled kebeles were involved. Data were collected using semi-structured interview, group discussion and field observation. The collected data were analyzed using preference ranking, paired comparison, direct matrix ranking, informant consensus factor and fidelity level index. A total of 89 species of medicinal plants were collected. These species distributed under 82 genera and 44 families were identified. Out of the collected 89 medicinal plants 60 species (67.42%) were used against human ailments, 10 species (11.24%) were used against livestock ailments and 19 species (21.34%) were used to treat both human and livestock ailments. Herbs constituted the largest growth habit (40species) followed by shrubs (33 species). The most frequently used plant part was leaves (39.9%) followed by roots (23.83%) and condition of preparation was fresh plant materials (70.98%). The most widely used method of preparation was crushing (22.8%) followed by crushing-squeezing (11.39%). The most common route of administration was oral (49.74%) followed by dermal (30.05%). The most commonly used application of medicinal plants was drinking (32.12%) followed by eating (13.98%). Ruta chalepensis was predominant medicinal plant cited by most of the informants (70%) while the disease categories with the highest ICF value (0.90) for evil eye. There was high preference for Euphorbia abyssinica for treating stomachache while paired comparison showed Ocimum lamifolium the most preferred species for treatment of febrile illness. Anthropogenic factors are the major threats to medicinal plants. In general, medicinal plants are still playing significant role in the management of various human and livestock diseases in the study area.