Tailings produced in the beneficiation of Carlin-type gold deposits are characterized by fine particle size and high mud content. When neutralized with wasted acid generated by pressurized pre-oxidation, the tailings turn to neutralized slag and perform as a novel backfill material. To understand the influential behavior of variable factors on the strength and its optimization of cemented neutralization slag backfill, RMS-BBD design test was carried out with 56–60% slurry mass fraction, 12.5–25% cement/(neutralization slag + waste rock) (i.e., C/(S+R)) and 30–40% waste rock content. A modified three-dimensional quadratic regression model was proposed to predict the strength of cemented neutralization slag backfill. The results showed that backfill strength predicted by the modified ternary quadratic regression model was in high coincidence with the data of backfill mixture tests. C/(S+R) was predominant in backfill strength with regard to every single influential factor throughout the curing age, and the mass fraction of slurry had a significant effect on the later strength. From the perspective of economic and engineering operation, a multi-objective function method was further introduced to optimize the backfill strength. The optimal mixture proportion of cemented neutralized slag backfill slurry was: 58.4% slurry mass fraction, 32.2% waste rock content, and 20.1% C/(S+R). The backfill strength of this mixture proportion on days 7, 28 and 56 was verified as 0.42, 0.64 and 0.85 MPa, respectively. RSM-BBD design and multi-objective function optimization proposed a reliable way to evaluate and optimize the strength of neutralized slag backfill with high mud content.