Septic system (SS) is the oldest anaerobic wastewater treatment system still widely employed today in suburban and urban areas. The sustainability of SS in developing countries, including Tanzania, is restricted by several constraints (e.g., poor installation and hydraulic overloading (technical issues), poor resource recovery practices (economic issue), maintenance and awareness (social issues), etc.). Efforts have been done to improve SSs’ sustainability, but the improvement is hindered by a lack of information on how to guarantee SSs sustainability mainly, at the household level. Therefore, this study was aimed to assess the SSs’ sustainability in residential buildings in Mwanza city, Tanzania emphasizing economic, environmental, technical, and social aspects. The sustainability assessment (SA) was accomplished by study area and sustainability indicators (SIs) selection methods, diverse data collection methods, and the Fuzzy-based Indices Approach (FIA) (data analysis method). The results from SA show that 18 out of 50 indicators were selected as appropriate indicators for SA of 200 households having SSs in the Nyegezi area. Also, the entire systems in the city had an index of 0.42 and fall in a danger state. It was concluded that the SIs assessed were relevant to the studied system. They demonstrate the importance of matching any set of indicators to the characteristics of the specific sanitation system being examined. Indeed, corrective measures must be suggested for immediate livelihood improvement and sustainability considerations. The study provided a tool and framework for assessing the sustainability of SSs in Tanzania using a set of most 18 relevant SIs.