Developing new thermoelectric materials with high performance can broaden the thermoelectric family and is the key to fulfill extreme condition applications. In this work, we proposed two new high-temperature thermoelectric materials—MgV₂O₅ and CaV₂O₅—which are derived from the interface engineered V₂O₅. The electronic and thermoelectric properties of V₂O₅, MgV₂O₅, and CaV₂O₅ were calculated based on first principles and Boltzmann semi-classical transport equations. It was found that although V₂O₅ possessed a large Seebeck coefficient, its large band gap strongly limited the electrical conductivity, hence hindering it from being good thermoelectric material. With the intercalation of Mg and Ca atoms into the van der Waals interfaces of V₂O₅, i.e., forming MgV₂O₅ and CaV₂O₅, the electronic band gaps could be dramatically reduced down to below 0.1 eV, which is beneficial for electrical conductivity. In MgV₂O₅ and CaV₂O₅, the Seebeck coefficient was not largely affected compared to V₂O₅. Consequently, the thermoelectric figure of merit was expected to be improved noticeably. Moreover, the intercalation of Mg and Ca atoms into the V₂O₅ van der Waals interfaces enhanced the anisotropic transport and thus provided a possible way for further engineering of their thermoelectric performance by nanostructuring. Our work provided theoretical guidelines for the improvement of thermoelectric performance in layered oxide materials.