A three-channel model of interaction of the O2 gas with zinc oxide during photoactivated oxygen isotope exchange (POIE) in a flow-through reactor was suggested including (1) photoadsorption, (2) exchange in the gas phase (homo-exchange), and (3) zinc oxide–gas exchange (hetero-exchange). In contrast to previous methods, the model includes photoadsorption as an increase in the rate of mixture renewal, which eliminates possible distortions of the time dependences of the calculated rates. Derivation of formulas and experimental data processing were given for POIE in the O2–ZnO system used as an example, under illumination in interband and exciton absorption regions and in the region of absorption by defects in the structure of ZnO.