Rural communities in the Koshi River basin, a trans-boundary river basin in the Hindu Kush-Himalayas, have been experiencing unprecedented difficulties for adapting with the livelihood challenges arising from floods, droughts and other climatic, environmental and socio-economic stresses. The single purpose adaptation approach often fails to address the multiple challenges arises from cascading effects of climate change at different scales and stages. To fill this gap, we developed a multi-dimensional flexible adaptation framework looking at the four dimensions of adaptation, structure, issue, time, and space (SITS). The SITS framework provides a comprehensive approach for cascading adaptation at trans-boundary river basin level and it could effectively enhance the adaptive capacity and transform livelihood outcome if properly implemented. Following the SITS framework, we examined four cascading adaptation pathways for: i) reducing disaster stressors on livelihoods, ii) enhancing access to crucial livelihood capitals, iii) improving equal rights to livelihood, and iv) strengthening synergies and exploiting complementarities at trans-boundary river basin level. The findings revealed that in the context of changing climate, it is necessary to employ different livelihood adaptation strategies and multiple responses simultaneously or sequentially to successfully adapt to the cascading effects of changing climate. The cascading adaptation may provide a sound basis on which to cope with the climate uncertainty through realistic scenarios of structure, issue, time and space. Its implementation, however, has several obstacles, for example, differences in national system, investment capacity, complexity of trans-boundary basin, remained particularly in trans-boundary river basin where managing transnational trade-offs and harness spatial synergies are critically important.