Herein, the catalytic performance of Fe/Nb/M (M= Mn, Co, Ni, and Cu) spinel ferrites prepared by a co-precipitation method for the high-temperature water-gas shift (HT-WGS) was investigated. Incorporation of Nb into the iron oxide lattice was found to moderately improve the catalytic activity. Conversely, the co-doping with Nb and transition metals (Mn, Co, Ni, and Cu) into the iron oxide matrix drastically enhanced the HT-WGS activity. The high lattice strain/disorder and facile Fe3+/Fe2+ redox cycle induced by the enhanced synergism in the Fe/Nb/M ternary catalysts serve as active sites to efficiently catalyze the WGS reaction. The results also indicate that the Nb acts as a textural promoter to improve the thermal stability of the active magnetite phase, while the transition metals act as structural promoters to enhance the WGS activity. The Fe/Nb/Ni exhibited the higher catalytic performance among the co-doped spinel ferrite catalysts. The high lattice strain/disorder, facile reduction of hematite to magnetite and highly facilitated surface Fe3+/Fe2+ redox pair by strong synergistic effect could be responsible for the better activity and stability of Fe/Nb/Ni in HT-WGS reaction. The characterizations of the spent Fe/Nb/Ni after 100 h of reaction revealed that the catalyst exhibited an excellent structural and surface stability during the reaction.