We investigated interactions between Ti6Al4V alloys and strontium zirconate (SrZrO₃) ceramic to assess its potential as a refractory mold material in investment casting. We developed a robust yet simple procedure to examine both the liquid–solid and solid–solid interactions using pellets in drop casting and diffusion couple methods. Reaction layers were characterized using optical microscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and x-ray diffraction (XRD). The results were compared to alumina (Al₂O₃) which is still a common refractory ceramic for molds in investment casting. Our findings indicate that Ti6Al4V surfaces in contact with SrZrO₃ had no apparent changes in surface chemistry nor microstructure. On the other hand, Ti6Al4V surfaces in contact with Al₂O₃ developed γ-TiAl and α₂-Ti₃Al intermetallics with thicknesses of ~ 100 μm in diffusion couples and ~ 10 μm in drop-casting experiments. Nanoindentation results showed that the surface of Ti6Al4V in contact with Al₂O₃ was significantly harder compared to SrZrO₃, confirming our conclusion. Given the time and costs associated with mechanical and chemical removal of reaction layers on Ti6Al4V castings, SrZrO₃ can be a better choice for a mold material in the investment casting of titanium alloys.