Bangladesh is planning to construct its second nuclear power plant (NPP) to improve its energy mix to mitigate the long-lasting energy crisis. From this perspective, this study aims to determine potential areas for the construction of a NPP in the south-central and southeastern parts of Bangladesh using a geographic information system (GIS) and the analytical hierarchy process. The analysis utilized 6 main data criteria, 22 sub-criteria, and 5 sub-sub-criteria. These factors ensure plant safety, environmental protection, and sustainable development. A suitability map of each sub-criterion and sub-sub-criterion was prepared according to a scale of 0 through 5, where 0, 1, 2, 3, 4, and 5 indicate excluded area, completely unsuitable area, unsuitable area, moderately suitable area, suitable area, and most suitable area, respectively, which were utilized to create a suitability map of each criterion. Finally, GIS-based overlay analysis, among the suitability maps of main data criteria, indicates 1112.42 km2 as the most suitable area from the study area, which consists of 43 potential areas for the establishment of a NPP. This study may facilitate policymakers in choosing a suitable site for establishing a NPP in the region under study and abroad.