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.