Abstract: The key to obtaining high-strength backfill is the cementing material used for backfilling. Therefore, to prepare a new slag-based binder for cemented tailings backfill, hydrated lime, desulfurized gypsum, sodium sulfate, and sodium hydroxide were selected as slag activators. Firstly, the D-optimal mixture design method was used to develop the strength regression model, analyze the influence of hydrated lime, desulfurized gypsum, sodium sulfate, and sodium hydroxide on the strength, and determine the best ratio of slag activator. Secondly, after optimizing the slag content, the optimum proportion of the binder was obtained. Lastly, X-ray diffraction and scanning electron microscopy were used to study the internal mechanism of the hydration products of the slag-based binder, the microstructure of backfill, and strength formation. The results show that the D-optimal mixture design method is a good method of obtaining the formula of the mixture with a less experimental amount. The sensitivity order to slag is sodium hydroxide > hydrated lime > desulfurized gypsum > sodium sulfate, and there are different degrees of interaction, so the weighing accuracy should be considered when batching. At the optimum mass ratio of binder (slag 85.00%, slaked lime 8.03%, sodium sulfate 3.96%, desulfurized gypsum 1.85%, and sodium hydroxide 1.16%), the early strength (1–3 d) is 3.5 times higher than that of cement, and the late strength (7–28 d) is at least two times higher than that of cement. The increased strength of hardened backfill cemented is closely related to ettringite (AFt) and C–S–H, the two primary hydration products of the new slag-based binder. During the early stages of hydration, a large amount of AFt rapidly nucleated on the surface of the slag, the distance between the tailing particles provided plenty of space for ettringite growth, and its long prismatic structure continuously extended into the intergranular pores. The rapid formation of early strength of backfill is primarily because of the physical filling effect of ettringite. In the later stage, the strength of the backfill is primarily attributed to the wrapping and bonding effect of C–S–H, which further optimizes the compact structure of the backfill. The high-strength backfill can be obtained using the new slag-based cementitious material, which is of great significance for safe and efficient mining. The slag-based binder that contains 86.94% (mass fraction) of industrial solid waste helps solve the problem of desulfurized gypsum of coal-fired power plants and mine tailings. Additionally, the D-optimal mixture design proved to be an effective method for designing and optimizing the ratio of multicomponent materials, such as binders and activator components.