Abstract: To reduce the cost of coal mine backfill mining, this study was conducted against the background of fully mechanized unit dense backfill mining at a mine in Shandong Province. Aiming at the design requirement that the 28-day uniaxial compressive strength (UCS) of the backfill should be no less than 4.5 MPa, a systematic investigation was carried out on the mix proportion optimization of slag powder replacing cement. Through raw material property tests, slump tests, and UCS tests, the reasonable ranges of the slurry mass concentration (72%～76%), slag powder content (percentage of the total mass of cementitious materials, i.e., cement + slag powder, 40%～60%), and binder-to-gangue ratio (mass ratio of cementitious materials to coal gangue, 0.20～0.24) were determined. Based on the response surface methodology (RSM), 27 sets of mix proportion experiments were designed. Regression prediction models for the UCS of the backfill at 3 days, 7 days, and 28 days were established, and the interaction effects among the factors were analyzed. The results showed that the optimal slag powder content was 50%, and the three factors exhibited a synergistic enhancement window for strength gain rather than a linear superposition. Through comprehensive technical and economic analysis, the optimal mix proportion was determined as follows: slurry mass concentration 74%, slag powder content 50%, binder-to-gangue ratio 0.20, and fly ash-to-gangue ratio (mass ratio of fly ash to coal gangue) 0.18. In field industrial application, the measured 28-day UCS of the backfill reached 5.92 MPa, satisfying the design requirement. The unit cost of filling materials was reduced from 71.42CNY/m³to 46.17CNY/m³, a decrease of 35%, saving over 4 million yuan annually. Meanwhile, the resource utilization of industrial solid waste was realized.