Because of the growing importance of sustainability in the global market, as well as the negative environmental consequences of cement manufacturing, partial replacement of Portland cement (PC) with supplementary cementitious materials (SCMs) such as silica fume (SF) has become increasingly popular. The purpose of this study was to build a framework for sustainable practices based on eighteen sustainability indicators, which included technical, economic, and environmental factors. Cementitious matrixes were generated by replacing PC with SF at different percentages of the mass of the matrix: 0, 5, 6.5, 7.5, 8.5, and 10%. Several laboratory experiments were carried out to obtain an accurate evaluation, including the measurement of setting times, compressive strength, capillary water absorption, and surface electrical resistivity on mortar specimens, which were used as technical indicators. The environmental implications of products were also evaluated using a life cycle approach, and sensitivity analysis was performed to develop a robust sustainability assessment model for SF substitution. In addition, According to the findings, SF has the potential to raise the sustainability score by at least 36.4% and as much as 118.2%. When compared to all of the other combinations evaluated, the specimen containing 8.5% SF achieved the greatest sustainability score and was the most sustainable mixture. The concept and technique used in this study can be applied to other SCMs of a similar nature.