This study evaluates the implications of multiple climatic and non-climatic factors on the water resource of the Lake Tana sub-basin, Ethiopia. The study focuses on three drivers: land use change, irrigation expansion, and climate change (CC), and their impact on the current and future water availability across the sub-basin. The study uses a random forest (RF) machine learning classifier in the Google Earth Engine (GEE) platform to detect land use land cover change (LULC) and for mapping the actual irrigated-area. The Climate Hazards Group InfraRed Precipitation and temperature data were used with station data to evaluate the implication of CC on the water availability of Lake Tana sub-basin. The supply-demand relationship was done for Gumara catchment within Tana sub-basin as an experimental site. Based on the LULC analysis, plantation, cropland, bare lands, built-up, and wetland showed an increasing trend, while forest, bush land, and grassland showed a decreasing trend. The increasing rate of crop land in the expense of natural forest, shrub land, grassland may cause runoff/flood, high soil erosion, and lower rate of groundwater recharge. The actual irrigated area mapping analysis shows a widespread irrigation near the Lake Shore and upstream parts of the sub-basin. The climate change analysis shows an increasing trend of potential evapotranspiration during the irrigation period attributed to increase in maximum temperature. The rising of potential evapotranspiration during the irrigation period creates a water shortage in the study and future periods as the crops need more water for growth. The estimated stream flow for Gumara catchment shows an increasing trend for the future period. The supply-demand relationship of the catchment shows an uneven distribution of water in the Gumara catchment both in the current and future periods resulting in unbalance abstraction of irrigation water. The study reveals that climate change, land cover change, and uncontrolled expansion of irrigated land area are likely to increase the unmet demand by increasing irrigation water demand, and this can cause conflict of interest between the users. Therefore, sustainable water resource management practices such as land management practices, and adaptive management of irrigation should be applicable to prevent or reduce the occurrence of conflict over the water demand.