We report the structure–activity relationship of copper pyrovanadate (Cu2V2O7) as an efficient catalyst for SO3 decomposition in solar thermochemical water splitting cycles. Of the α, β, and γ polymorphs of Cu2V2O7, the α-phase, which has a blossite-type structure, was stable under the catalytic reaction conditions. Spontaneous oxygen desorption accompanied by charge compensation through the reduction of Cu2+ to Cu+ produced an oxygen deficiency corresponding to Cu16V16O55 at 600 °C. Density functional theory calculations based on these results showed that oxygen vacancy formation is more favorable on the Cu–O–V bridging sites than on the V–O–V site in the pyrovanadate unit. The oxygen vacancy formation energy of the (100) surface is considerably less than that of bulk Cu16V16O56. The reaction, Cu16V16O55 + SO3 → Cu16V16O56 + SO2, is exothermic, suggesting that oxygen vacancies play a key role in catalytic SO3 decomposition over a Cu2V2O7 catalyst.