The Ganges Brahmaputra (GB) River Basin of South Asia is experiencing climate uncertainties and extremes which are disproportionately affecting agriculture, the state of food security, and the livelihoods of small-scale farmers. Climate-smart agriculture (CSA) is undoubtedly important to deal with these challenges by increasing productivity, adapting to extreme climate conditions and mitigating greenhouse gas (GHG) emissions. Currently, CSA has been highly adopted to reduce the climate change effects on the agricultural sector and enhance the resilience of small-scale farmers. Assessing the profitability of these practices is imperative to decide whether to continue or drop the adopted practices. This study aimed to assess the profitability of CSA practices through cost and benefit analysis adopted by small-scale farmers in the Ganges Brahmaputra River basin of South Asia, particularly in Bangladesh, India, and Nepal. A thorough understanding of the costs and benefits of CSA options is urgently needed to identify the best adaptation options for both short and long-term interventions in the agriculture sector amid climatic uncertainties. The outcomes of the research would support the farmers to make decisions on the most profitable option and for policymakers to formulate effective climate change-linked agricultural policies and programs. Thus, this research fosters links between science, practice, and policy linkages for sustainable food security and small-scale farmers’ resilience to climate change.