Mekelle City is among the most rapidly growing cities in Ethiopia though the management of wastewater is very poor. The city lacks proper infrastructures for the collection and treatment of urban wastewater so that the wastewater released from different sectors directly joins the urban drainage of the city that finally flows to the Ellala River, which crosses the city. However, such practices have the potential to contaminate water reservoirs and surface water and groundwater bodies that endangers the health of the nearby society. Hence, to reduce and manage the wastewater impact sustainably, introducing natural treatment mechanisms like waste stabilization pond technology (WSP) is an ultimate means to implement with low cost and technology demand. Hence, the objective of this study was to select suitable sites for WSP sites to treat domestic wastewater of the city. During the process of WSP selection, nine most important parameters were considered namely groundwater, hydrogeology, slope, elevation, soil depth, land use land cover (LULC), distance from the settlement, from the road, and from the river. Those determinant factors affecting site selection were generated from satellite images, maps, and Digital Elevation Model. Supervised image classification for Landsat TM satellite image was done while the rest variables’ geo-database files were generated in ArcGIS interface software. Since all input variables have not equal influence in WSP site selection, the weighted value of variable estimation was undertaken using the algorism weighted combination formula. And finally, the weighted overlay model was used to run the model so that suitable sites were selected. Result shows that the city has a large number of alternative sites for establishing a waste stabilization pond. Five classes of suitability were generated (from low to very high suitability level). The North West and Northern parts of the city are found in the potential candidates’ areas as of the central and southern parts. Geographically, these areas are topographically gentle slope and have low altitude plus the newly designed sewer line network outlet lies in this direction. In contrast, unsuitable areas are found in the East, Central, and South direction of the study area. These selected areas are characterized by high population density, steep slope, and high topography. Groundwater, elevation, hydrogeology, and slope were found the most influential parameters determining WSP site selection. On the other hand, distance from road and river, land use cover, and soil depth were found the least influential parameters that determine WSP selection. Out of the total mml area, 21.3% were found highly suitable. So, this implies that the city has a large potential area that can be used for WSP establishment. From the present study, it can be concluded that GIS is a very essential tool in urban utility establishment like urban domestic wastewater treatment site selection. Although the city has adequate potential areas for establishing WSP, further assessment of flood vulnerability, biochemical determination, wastewater amount quantification, population growth, and urban expansion need to be seriously considered before implementing.