Utilization of medicinal plants is almost as old as the history of mankind. Semi-structured interview, guided field walk, group discussion and market survey were used to collect ethnobotanical data in Tahitay Adiyabo and Kafta Humera districts in northern Ethiopia. A total of 47 informants (30 males and 17 females) were selected purposefully from three sub-districts: Lemlem (n = 27), Adi-Goshu (n = 10) and Hilet-Coca (n = 10). A total of 115 species of medicinal plants were collected and identified for treating 59 humans and livestock ailments. The most commonly used plant parts for herbal preparations were roots (35.5%) and leaves (21.74%) and were administered through oral, dermal, ocular, nasal and vaginal routes in decreasing order. Oral application (58 preparations, 50.43%) was the highest and most commonly used route of application followed by dermal application (35 preparations, 30.43%). Kunama tribes are rich in medicinal plant species and the associated indigenous knowledge. Future studies should focus on phytochemical extraction of herbal drugs for their efficacy and possible toxicity.