Groundwater is the most crucial resource for human beings and plays an important role in combating climate change and is substantial to human existence on the globe. Overall increased demand for water in different sectors, population growth, and unreliable rainfall necessitates the planning and management of groundwater. In this study, groundwater potential zones are delineated by combining remote sensing and geographical information system techniques in the Guder watersheds of the Upper Blue Nile Basin. Groundwater potential zones are prepared by using various multi-influencing factors like geomorphology, land use/cover, lithology, soil type, soil texture, drainage density, slope, lineament, rainfall, and elevation. These influencing factors’ features were given appropriate weightage according to Saaty’s AHP method, expert judgment, and their relative significance for groundwater occurrence. The groundwater potential zone was classified into different categories as very poor, poor, moderate, good, and very good according to quantile classification. This study reveals that about 33.6% of the Guder River Basin represents a good andvery good GWPZ category with an equal value of 16.8%,; while values 23.3%, 20.2%, and 22.9% were denoted by very poor, poor, and moderate groundwater potential zone, respectively. GWPZ was validated by field-collected data such as well discharge and soil depth. An accepted similarity was observed between delineated GWPZ and the basin’s soil depth graphically. The results of this study were also verified by correlation and kappa statistics values of 0.73and 77%, respectively. The study is certain with a sensible dimension of consistency in pairwise comparison between influencing and the overall weightage. The very high GWPZs are found in the northern part starting from the center longitude of the study area, more along with the northwestern, southern, and southwestern of the Guder subbasin. Low to very low groundwater potentiality has been seen at different distances from the center due to the presence of escapements, hills and steep side slopes, slopes, and rock surfaces. The study also revealed that the zone of high groundwater potential has high soil depth, and the zone of low groundwater showed low soil depth as the capacity of the aquifer to store water may depend on the depth of soil profile. This study attests to the GIS and remote sensing techniques as an effective model for delineation of GWPZs and can be applied at other basins of Ethiopia.