This study addresses the corrosion problem of refractory materials during high-temperature molten treatment of pharmaceutical waste salt, and systematically investigates the interface behavior and corrosion mechanism of MgO-based refractory materials in simulated pharmaceutical waste salt (65 wt% NaCl-30 wt% Na₂SO₄-5 wt% CaCO₃). Through sessile drop wetting infiltration experiments, static corrosion tests (950 °C and 1150 °C/48 h), combined with SEM-EDS, XRD characterization, and FactSage thermodynamic calculations, the corrosion resistance of high-purity MgO phase (HM-97) refractory materials and magnesium–aluminum spinel composite phase (MA-85) refractory materials was compared and analyzed. The results show that due to the fine periclase grains and rich grain boundaries, the molten salt infiltration rate of HM-97 material in the 644–800 °C range is significantly higher than that of MA-85. After corrosion at 950 °C, HM-97 and MA-85 formed 47 μm and 53 μm transition layers respectively, and the HM-97 surface generated Ca₃Mg(SiO₄)₂ phase leading to uneven corrosion morphology. At 1150 °C, HM-97 produced long cracks and the transition layer thickness remained almost unchanged due to dissolution, while MA-85 formed an approximately 72 μm transition layer and a dense metamorphic layer. Phase analysis and thermodynamic calculations suggest that the MgAl₂O₄ phase in MA-85 is likely stable at high temperatures, which appears to effectively prevent molten salt infiltration and contribute to forming a protective metamorphic layer, thereby potentially enhancing the material’s corrosion resistance. The MgAl₂O₄ phase is proposed to improve the service performance of MgO-based refractory materials in the molten pharmaceutical waste salt environment.