Climate change and related extreme events have become global challenges in ensuring sustainable development. This affects water availability and agricultural production, particularly in developing countries. This study explored the factors affecting farmers' adaptation mechanisms to climate change in different agro-ecological zones of the Bure Zuria district of northwestern Ethiopia. A household survey, focus group discussion, key informant interviews, and observations were used to acquire primary data on farmers' socioeconomic and demographic characteristics, adaptation strategies and potential barriers. About 190 randomly selected households from different agro-ecologies were included in this study. Moreover, reports and published sources were used to acquire secondary data. Data were analyzed using a multinomial logit regression model and descriptive statistics. The results indicated that soil and water conservation practices (26.7%) were the main adaptation responses in highland agro-ecology. In contrast, supplementary feeding for livestock (56%) was the main adaptation response to the adverse effects of climate extremes in lowland agro-ecology. Farmers identified land scarcity (25.84%) and shortage of water for irrigation (28.57%) as major barriers to adaptation in the highland and lowland agro-ecologies, respectively. In addition, agro-ecology, education level, age, active labor, number of livestock (TLU), off-farm income, frequency of extension contacts, credit access, and market access were decisive factors affecting farmers’ adaptation mechanisms to withstand extreme climatic events. In conclusion, soil and water conservation practices are more practiced in highland areas than in lowland areas. Because the steepness of farmlands and erodible soils increase farmers' vulnerability to flood hazards in highland areas than in lowland areas. It is suggested that investigations on the climate change-induced gender-differentiated impacts shall be conducted to design all-inclusive and effective responses.