The current study investigated the development of a sustainable thermo-chemical approach to effectively optimize MgO-waste activated GGBS formulations, using four types of magnesium oxide (MgO) waste materials with (ground granulated blast-furnace slag—GGBS) to develop bi-nary cementitious systems (MgO-GGBS). This stems from the expected complexity of cementitious binder optimization outcomes into a simpler analytic form, enhancing the rapid delivery of optimization results and contributing to the global awareness of sustainable approaches and use of industrial wastes. Three levels of Portland cement by weight (90, 80, and 70wt.%) was replaced with MgO wastes including an industrial by-product (GGBS) to develop an experimental regime. Investigation was carried out by employing an experiment-based optimisation technique (thermo-chemical approach), which involved the design of an experimental regime and application of experimental tests (pH measurements, thermogravimetric and derivative thermogravimetric analysis—TG/DTG and isothermal calorimetry), establishment of design variable/parameters, measurement of the design performance of the identified design parameters, and review of the relationship between the independent (control) and dependent variables (MgO wastes and their compositions). The experimental test results successfully optimised the binder compositions, established the best performing binder system (MG1), and provided an in-depth insight into the thermal stability and hydration kinetics of the investigated binder systems.