Nepal’s Karnali Province, nestled in the northwestern Himalayas, is a region of captivating beauty and stark challenges. Encompassing nearly one-fifth of Nepal’s land area, Karnali boasts rich cultural heritage, diverse ethnicities, and a unique mosaic of ecological zones. However, the region grapples with significant socio-economic hardships, including low economic growth, widespread poverty, and limited infrastructure development. This vulnerability is further exacerbated by the looming threat of climate change, which poses risks to ecosystems and the livelihoods heavily reliant on natural resources. This chapter examines the intricate interplay of ecological, cultural, and socio-economic factors in the Karnali region of Nepal. By exploring the potential of sustainable livelihoods, ethno-ecological conservation, and transboundary cooperation, it aims to contribute to a more sustainable and equitable future for the region. By integrating traditional ecological knowledge (TEK) with scientific data and sustainable resource management practices, communities in Karnali can navigate the challenges and carve a path toward a more prosperous and ecologically sound future.