The interfacial reaction between Ti-6Al-4V alloy and ZrO2 ceramic mold with zirconia sol binder was investigated by keeping the 12 g alloy melt in a vacuum induction furnace for 15 s. The microstructures, element distribution and phase constitution of the interface were identified by optical microscopy (OM), scanning electron microscopy (SEM) equipped with energy dispersive spectroscopy (EDS) and X-ray diffraction (XRD). The results show that the whole interface reaction layer can be divided into three regions: metal penetration layer, transition layer, and hardened layer according to the structure morphology, which has the characteristics of severe metal penetration, finer lamellar, and coarse oxygen-rich α phase, respectively. The erosion of the alloy melt on the ceramic mold promotes the decomposition of zirconia, which leads to the increase of local Zr concentration, greatly increasing the activity coefficient of Ti, aggravating the occurrence of interfacial reaction. Thus, the interfacial reaction shows the characteristics of chain reaction. When the oxygen released by the dissolution of zirconia exceeds the local solid solubility, it precipitates in the form of bubbles, resulting in blowholes at the interface. The result also indicates that the zirconia mold with zirconia sol binder is not suitable for pouring heavy titanium alloy castings.