This study was conducted on medicinal plants and their uses to treat human and livestock ailments in five kebeles of Damot Sore District in Wolaita Zone, SNNPR. The aim of this study was to collect, identify uses of indigenous knowledge, and document the practice of traditional medicinal plant species. A total of 163 households (124 males and 39 females) between the ages 28 to 85 were selected from the complete list of five Kebeles. Similarly, 25 traditional healers were selected purposively with the help of kebele administration leaders and elder peoples. Ethnobotanical data were collected using, semi-structured interview, group discussion, field observation, and market survey. The collected data were analyzed by preference ranking, paired comparison, Fidelity level index, informant Consensus factor, and direct matrix ranking method. All data were analyzing by using SPSS soft ware. A total of 60 medicinal plant species belonging to 52 genera, and 33 families were documented in this study. Out of these, 28(46.6%) were collected from wild, 20(33.33%) were cultivated and 12(20%) were collected from both wild and home garden. The growth habit of them, 31 (51.67) were herbs, followed by 14(23.33) trees, and 13(21.67) shrubs. Leaves were the most widely used part followed by roots, seeds, fruits, barks. The total Medicinal plants species 35(58.33%) and 10(16.67%) were used to treat human and livestock ailments respectively. The most commonly used methods of remedy preparation were grinding 26(38.23%), followed by chewing 12(17.64) and pounding 10(14.7%). The most common route of administration was oral (56.67%) followed by dermal (33.33%). The most commonly used application of medicinal plants was drinking (36.76%). The informant consensus obtained from this study showed that Allium sativum was cited by 65 respondents (39.88%) for treating cough and malaria, followed by Ruta chalepensis, cited by 57 (35%) of respondents for treating stomachache, and the evil spirit 'Goromootiya' or 'Buda' in the area. An analysis of preference ranking showed that Allium sativum is the most effective medicinal plant for the treatment of the common cold, followed by Zingiber officinale.The highest fidelity level value showed 100% that Carissa spinarum was used against tonsillitis followed by Withania somnifera which was 95%. Arthropogenic factors are major threats to MPs in the study area. Key words: Damot sore district, Indigenous knowledge, Ethnobotany, Medicinal plants