In this work, the functional character of complex -Fe2O3(0001)/SrTiO3(111) and Au(111) islands/ -Fe2O3(0001)/SrTiO3(111) heterostructures has been proven as gas sensors at room temperature. Epitaxial Au islands and -Fe2O3 thin film are grown by pulsed laser deposition on SrTiO3(111) substrates. Intrinsic parameters such as the composition, particle size and epitaxial character are investigated for their influence on the gas sensing response. Both Au and -Fe2O3 layer show an island-type growth with an average particle size of 40 and 62 nm, respectively. The epitaxial and incommensurate growth is evidenced, confirming a rotation of 30 between the in-plane crystallographic axes of -Fe2O3(0001) structure and those of SrTiO3(111) substrate and between the in-plane crystallographic axes of Au(111) and those of -Fe2O3(0001) structure. -Fe2O3 is the only phase of iron oxide identified before and after its functionalization with Au nanoparticles. In addition, its structural characteristics are also preserved after Au deposition, with minor changes at short-range order. Conductance measurements of Au(111)/ -Fe2O3(0001)/SrTiO3(111) system show that the incorporation of epitaxial Au islands on top of the -Fe2O3(0001) layer induces an enhancement of the gas-sensing activity of around 25% under CO and 35% under CH4 gas exposure, in comparison to a bare -Fe2O3(0001) layer grown on SrTiO3(111) substrates. In addition, the response of the heterostructures to CO gas exposure is around 5–10% higher than to CH4 gas in each case.