Ni-based superalloy, which has excellent high-temperature strength and corrosion resistance, is mainly used in aviation materials, high-performance internal combustion engines, and turbines for thermal and nuclear power generation. For this reason, refining the impurities in Ni-based superalloys is a very important technical task. Nevertheless, the original technology for the melting and refining of Ni-based superalloys is still insufficient. Therefore, in this study, the effect of the CaO-Al2O3-MgO-TiO2 slag on the removal efficiency of an impurity element sulfur in Incoloy® 825 superalloy, one of the representative Ni-based superalloys, was investigated. The desulfurization behavior according to the change of TiO2 content and CaO/Al2O3 (=C/A, basicity) ratio as experimental variables was observed at 1773 K (1500 °C). Although the TiO2 content in the slag increases to 15 mass pct, the mass transfer coefficient of sulfur in molten alloy showed a constant value. Alternatively, under the condition of C/A > 1.0 of slag, the mass transfer coefficient of sulfur showed a constant value, whereas under the condition of C/A < 1.0, the mass transfer coefficient of sulfur greatly decreased as CaO decreased. Hence, in the desulfurization of Incoloy® 825 superalloy using the CaO-Al2O3-MgO-TiO2 slag, the TiO2 content in the slag does not have a considerable effect on the desulfurization rate and desulfurization mechanism (metal phase mass transfer controlled regime), but the basicity of the slag has a significant effect on desulfurization mechanism. When the slag basicity decreases below the critical level, i.e., C/A < 1.0, which is corresponding to sulfur distribution ratio, Ls < 200, it was confirmed that the desulfurization mechanism shifts from the metal phase mass transfer-controlled regime to the slag phase mass transfer-controlled regime due to the variation in the physicochemical properties of the slag such as viscosity and sulfide capacity. In addition, the different desulfurization rates between steel and Ni alloy melts were discussed by employing the diffusivity of sulfur in both systems.