The dynamic behavior of metal-oxide interfaces under reverse water-gas shift (RWGS) conditions is crucial for rational catalyst design but remains poorly understood. Through first-principles calculations and interpretable machine learning, we reveal how reactant-induced stabilization governs structure-activity relationships at these interfaces. Our study identifies two key descriptors—oxygen vacancy formation energy (E_V) of the oxide support and atomic radius (r) of the supported metal—that collectively determine RWGS performance. Activity exhibits a volcano-type relationship with E_V, peaking at ~3.4 eV. The reaction mechanism shifts from carboxylate-mediated pathways on low E_V oxides to direct CO₂ dissociation on high E_V supports. Larger metal atoms (Pt, Pd, Ru) stabilize transition states by shortening O-H bond distances, significantly lowering barriers for lattice oxygen hydrogenation. Oxygen vacancies play dual roles: stabilizing intermediates and promoting vacancy regeneration throughout the catalytic cycle.

These findings establish a physically-grounded predictive framework linking reactant-induced interface dynamics to catalytic performance, enabling rational design of efficient RWGS catalysts.