An ethnobotanical study of medicinal plants was conducted to document the indigenous plant-based medicinal knowledge of the people of Dejen District from October 2013 to July 2014. A total of 80 informants (65 males and 15 females) between the ages of 22 and 84 were selected to collect information on medicinal plant use from ten sampled kebeles. Out of these, 20 key informants were purposively selected based on recommendation from elders and local authorities. Other informants were selected randomly. Ethnobotanical data were collected using semi structured interviews, field observations, group discussions and field walk interview. Data were analyzed using informant consensus, preference ranking, direct matrix ranking, fidelity level index and Jaccard’s coefficient of similarity combined with descriptive statistical analysis. A total of 118 plant species belonging to 107 genera and 57 families were recorded. From these, 75 species were recorded for the treatment of human aliments, 14 species for livestock and 29 species for the treatment of both human and livestock. Fabaceae and Lamiaceae appeared to be the most families. The majority of plants (51.7%) were found to be harvested from the wild. Fifty (50) plant species were herbs, 36 species shrubs, 28 species trees and 4 species climbers. The most frequently used plant parts were leaves (36.25%) followed by roots (16.3%). The most widely used method of preparation was crushing (26.9%) of the different plant parts followed by powdering (17.4 %). The common route of administration recorded was oral (45%) followed by dermal (30%) and nasal (6.7 %). Informant consensus showed Ruta chalepensis and Allium sativum to be the most frequently reported (65% each) species followed by and Lepidium sativum. Preference ranking showed Lepidium sativum to be the most preferred species to treating several diseases. Direct matrix analysis revealed that Cordia africana to be the most important species. Fidelity level index showed Carissa spinarum and Moringa oleifera to have high medicinal use value against Malaria and Hypertension, respectively. The main threats to medicinal plants in the study area were reported to be agricultural expansion, firewood, grazing, drought and construction. It is therefore, recommended that the local people have to be encouraged to cultivate medicinal plants in their homegarden. Key words/phrases: Ethnobotany, Dejen, indigenous knowledge, medicinal plant, ailments, treatment