The mechanism on interfacial synergistic catalysis for supported metal catalysts has long been explored and investigated in several important heterogeneous catalytic processes (e.g., water-gas shift (WGS) reaction). The modulation of metal-support interactions imposes a substantial influence on activity and selectivity of catalytic reaction, as a result of the geometric/electronic structure of interfacial sites. Although great efforts have validated the key role of interfacial sites in WGS over metal catalysts supported on reducible oxides, direct evidence at the atomic level is lacking and the mechanism of interfacial synergistic catalysis is still ambiguous. Herein, Ni nanoparticles supported on TiO2- x (denoted as Ni@TiO2- x) were fabricated via a structure topotactic transformation of NiTi-layered double hydroxide (NiTi-LDHs) precursor, which showed excellent catalytic performance for WGS reaction. In situ microscopy was carried out to reveal the partially encapsulated structure of Ni@TiO2- x catalyst. A combination study including in situ and operando EXAFS, in situ DRIFTS spectra combined with TPSR measurements substantiates a new redox mechanism based on interfacial synergistic catalysis. Notably, interfacial Ni species (electron-enriched Niδ- site) participates in the dissociation of H2O molecule to generate H2, accompanied by the oxidation of Niδ--O v-Ti3+ (O v: oxygen vacancy) to Niδ+-O-Ti4+ structure. Density functional theory calculations further verify that the interfacial sites of Ni@TiO2- x catalyst serve as the optimal active site with the lowest activation energy barrier (∼0.35 eV) for water dissociation. This work provides a fundamental understanding on interfacial synergistic catalysis toward WGS reaction, which is constructive for the rational design and fabrication of high activity heterogeneous catalysts.