In this study, a strategy to prepare CuO/Cu2O/Cu microwires that are fully covered by a nanowire (NW) network using a simple thermal-oxidation process is developed. The CuO/Cu2O/Cu microwires are fixed on Au/Cr pads with Cu microparticles. After thermal annealing at 425 °C, these CuO/Cu2O/Cu microwires are used as room-temperature 2-propanol sensors. These sensors show different dominating gas responses with operating temperatures, e.g., higher sensitivity to ethanol at 175 °C, higher sensitivity to 2-propanol at room temperature and 225 °C, and higher sensitivity to hydrogen gas at ∼300 °C. In this context, we propose the sensing mechanism of this three-in-one sensor based on CuO/Cu2O/Cu. X-ray diffraction (XRD) studies reveal that the annealing time during oxidation affects the chemical appearance of the sensor, while the intensity of reflections proves that for samples oxidized at 425 °C for 1 h the dominating phase is Cu2O, whereas upon further increasing the annealing duration up to 5 h, the CuO phase becomes dominant. The crystal structures of the Cu2O-shell/Cu-core and the CuO NW networks on the surface were confirmed with a transmission electron microscope (TEM), high-resolution TEM (HRTEM), and selected area electron diffraction (SAED), where (HR)TEM micrographs reveal the monoclinic CuO phase. Density functional theory (DFT) calculations bring valuable inputs to the interactions of the different gas molecules with the most stable top surface of CuO, revealing strong binding, electronic band-gap changes, and charge transfer due to the gas molecule interactions with the top surface. This research shows the importance of the nonplanar CuO/Cu2O layered heterostructure as a bright nanomaterial for the detection of various gases, controlled by the working temperature, and the insight presented here will be of significant value in the fabrication of new p-type sensing devices through simple nanotechnology.