Nanostructured In2O3 was grown on TiO2 NPs by thermal treatment of the solids mixture of TiO2 with the parent In(OH)3. The effect of calcination temperature in the range between 400 °C and 700 °C was investigated and peculiar changes both in the structure and in the catalytic activity of the TiO2/In2O3 heterostructure were revealed. It was found out that T = 600 °C is the best operating temperature for hydrogen production and in combination with 3.5 wt% In2O3 the H2 production from water reached the value of 3.5 mmol/h.g irradiating in the UV–Vis region. Once 5.0 wt% Cu2O nanoparticles were loaded on TiO2/In2O3, the photocatalytic activity boosted to 9.6 mmol/h.g of H2, overcoming the hydrogen production of pristine TiO2 by a factor of 48. This result can be attributed to the formation of a highly efficient heterojunction that assures a synergistic cooperation among the three semiconductors yielding an improved charge separation and faster charge transport, as evidenced by Mott-Schottky, PL and EIS measures.