Large-scale application of filled coal mining technology has long been limited by conditions such as the cost of filling. Compared to traditional filling materials, coal flotation tailing filling materials (CFTFM) offers advantages such as low cost and excellent performance. The Box–Behnken response surface method was used to investigate the influence of flotation tailing properties on the mechanical properties and hydration mechanisms of the filling material. Ash content, blending, and calcination temperature of the flotation tailings were used as the investigating factors, and uniaxial compressive strength (7d and 28d), slump, and the slurry water secretion rate of the filling material as the evaluation indicators. The results showed that the influence of the flotation tailings on the uniaxial compressive strength (28d) of CFTFM followed the order ash > calcination temperature > doping, with the interaction of ash and calcination temperature having a greater influence on the uniaxial compressive strength. The optimized pre-treatment conditions for the flotation tailings were 59% ash, 30% doping, a calcination temperature of 765 °C, and optimum uniaxial compressive strength of 7.02 MPa. The effect of flotation tailings on the exotherm of CFTFM hydration was determined using a TAM Air isothermal microcalorimeter, mainly in the induction and acceleration phases. Combined with SEM electron microscopy and IR FT-IR analysis of the hydration products, a descriptive model of the CFTFM hydration mechanism was established. CFTFM hydration can be described in three phases: diffusion, hydration, and hardening. The CFTFM prepared in this study is applicable to the integrated mining and charging synergistic mining technology, which can effectively reduce gangue lifting energy consumption and washing process waste, reduce the cost of filling, and can effectively achieve harmless, resourceful, and large-scale disposal of coal-based solid waste.