The study area (Fetam-Yisir watershed) is located in the central part of Upper Blue Nile Basin (UBNB), Northwestern Ethiopia. Increased demand of water, insufficient of water resource, lack of water quality, deficient in analyzing and understanding of groundwater dynamics and salinity source identification are the key issues in the area. Therefore, this study aims to develop the groundwater visibility zone, mechanism of groundwater movement/circulation and to identify the source of salinity using remote sensing (RS) and geographic information system (GIS) based multi criteria decision analysis (MCDA), integrated hydrogeochemical and isotopic methods with the help of hierarchical cluster analysis (HCA) and principal component analysis (PCA) techniques. To realize this, 28 and 26 water samples have been used for hydrochemical analysis and stable isotope (δ2H and δ18O) signature respectively. The watershed is characterized by tertiary volcanic rocks and recent quaternary deposits. The lithologic units include elluvial soil, alluvial soil, pyroclastic rocks, upper basalt and lower basaltic rocks. The area has E-W major fault that characterize and play the dominant role for the saline aquifers. The GWP zone which is delineated from the 9 thematic layers by weighting overlay using analytical hierarchy process (AHP) tool of MCDA technique confirms that 425.6 km2 (43.2%) area of Fetam-Yisir watershed falls in a „„good‟‟ GWP zone; 412.7 km2 (41.8%), 73.3 km2 (7.44%), 73 km2 (7.4%) and 0.2 km2 (0.02%) of the area falls in „„moderate‟‟, „„very good‟‟, “poor” and „„very poor‟‟ GWP zones, respectively. The high GWP is found in the Southeastern and Southwestern part of the study area including of the saline zone. The sensitivity analysis reveals that GWP map is more sensitive to slope with a mean variation index of 1.45%. From the hydrochemical data analysis, Three major water types were identified, these are: Mg-NaHCO3, Na-Mg-HCO3, and Na-HCO3. Mg-Na-HCO3 and Na-Mg- HCO3 are the dominant water types in the area. The high TDS Na-HCO3 type water is due to the high geochemical evolution (long sub-surface residence). From the primary and secondary hydrochemical data, waters of the area are generally evolves from Ca-HCO3 and Ca-Mg- HCO3 in the recharge area to Na-Mg-HCO3 and Na-HCO3 of the discharge area. From HCA and PCA techniques; HCO3-, Na+, TDS, EC, and Mg2+ were identified as the foremost hydrogeochemical parameters that dominantly characterize the area. Silicate hydrolysis (water-rock interaction), cation exchange, dissolution and precipitation are the main controls of the hydrogeochemical property of the waters in the area. The isotopic signature shows that most samples are nearly resemble with the average values of summer rain of local meteortic water line (LMWL) of the international atomic energy agency (IAEA) station at Addis Ababa, hence the aquifer system in the area is originated from summer rain and/intense rainfall event. Some samples are under a high depletion zone that are recharged at the high altitude source