Detecting the potential region of the groundwater resource is a difficult issue all over the world. Know a day, advanced geospatial technologies are excellent tools for efficient planning, managing, and assessing groundwater resources, particularly in data-scarce developing nations. Remote sensing (RS) and GIS-based multi-criteria decision analysis (MCDA) methods were applied to delineate the groundwater potential (GWP) in the Fetam-Yisir catchment, Blue Nile Basin, Ethiopia. Nine thematic layers: slope, geomorphology, normalized difference vegetation index (NDVI), topographic elevation, geology, land use/land cover (LULC), soil, rainfall, and drainage density from satellite and conventional data were used. The analytical hierarchy process (AHP) of an MCDA was employed to compute the corresponding normalized weight for the class in a layer and weights for the thematic layers on the base of their relative significance to the GWP. Integration of all thematic maps has been done using the ‘‘Weighted overlay’’ tool to obtain a GWP map. The GWP map is then validated using observed boreholes, and springs yield data. The verification of the final GWP zone map against yield data confirms 81.82% agreement indicating the authenticity of the method. The final GWP output confirmed that 43.2% area of the Fetam-Yisir catchment falls in a ‘‘good’’ GWP zone; 41.8%, 7.44%, 7.4%, and 0.02% of the area falls in ‘‘moderate’’, ‘‘Very good’’, “Poor” and ‘‘very poor’’ GWP zones, respectively. The sensitivity analysis divulges that the GWP map is highly sensitive to slope with a mean variation index of 1.45%. Thus, this study can be used for effective groundwater exploration, development, and sustainable abstraction, as well as it guides the researchers in locating the GWP zone.