Ab initio predictions indicating that alloying RuO2 with La, Eu, or Lu can increase the Seebeck coefficient α manifold due to quantum confinement effects are validated in sputter-deposited La-alloyed RuO2 films showing fourfold α increase. Combinatorial screening reveals that α enhancement correlates with La-induced lattice distortion, which also decreases the thermal conductivity twentyfold, conducive for high thermoelectric figures of merit. These insights should facilitate the rational design of high efficiency oxide-based thermoelectrics through quantum-guided alloying.