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Background: Medicinal plants are being used by the majority of the population throughout the world for their primary health care needs. The reliance is also prevalent in Nepal, aided by its ethnic and biological diversity. This study aimed to catalogue the ethnomedicinal knowledge of plants used by local people of Machhapuchchhre Rural Municipality of Kaski district. Methods: Data were collected between February 2017 and April 2018 from eight different villages of the Kaski district by using semi-structured interviews, guided field works, focus group discussions, and in-depth interviews. The reported traditional uses were supported by local assistants, cataloguing vernacular names and crosschecking with the earlier published and gray literature. Results: A total of 105 medicinal plants, belonging to 58 families and 99 genera were documented to treat 70 different diseases and ailments. The highest numbers of plants (37) were used for gastrointestinal disorders and the lowest (4) were used for female genital disorders. Commonly used parts were underground portions (28 species) followed by fruits and seeds (25 species each). The most preferred dosage form was juice, used for 50 ailments, and the oral route was the most favored route of administration (77 species). The medicinal properties of 22 plant species were found hitherto unreported in the district. Conclusions: The study area was found to be rich in plant resources and the people have ample knowledge on the use of medicinal plants. Due to a lack of proper documentation, conservation, and cultivation practices, valuable plant species are at risk of extinction. Thus, appropriate conservation measures and scientific assessment of plant-lore in the district is immediately required.