Tailing storage facilities are very complex structures whose failure generally leads to catastrophic consequences in terms of casualties, serious environmental impacts on local biodiversity, and disruptions in the mineral supply. For this reason, structures at risk must be reinforced or decommissioned. One possible option is its reinforcement with compacted filtered tailings stabilized with binders. Alkali-activated binders provide a more sustainable solution than ordinary Portland cement but require an optimization of the tailing–binder mixture, which, in some cases, can lead to a substantial experimental effort. Statistical models have been used to reduce the number of those experiments, but a rational design methodology is still lacking. This methodology to define the right mixture for a required strength should consider both the mixture components and in situ conditions. In this paper, response surface methods were used to plan and interpret unconfined compression strength test results on an iron tailing stabilized with alkali-activated binders. It was concluded that the fly ash content was the most important parameter, followed by the liquid content and sodium hydroxide concentration. From the obtained results, several statistical models were defined and compared according to the definition of a strength prediction model based on a mixture index parameter. It was interesting to observe that models with the porosity cement index still provide reasonable adjustment even when different tailings’ water contents are considered.