The n-n TiO2-SnO2 heterostructures composed of SnO2 nanoparticles (NPs) topped with TiO2 NPs have been produced by a novel hybrid reactive magnetron sputtering and pulse laser deposition for sensing acetone (C3H6O) vapors in the environment. The gas sensing characteristics of the TiO2-SnO2 heterostructures were measured over a range of operating temperatures (200–500°C) and the optimal working temperature of 300 °C was fixed. Further, the adsorption of acetone gas on both (110) and (101) stoichiometric and reduced surfaces of TiO2-SnO2 are studied by density functional theory (DFT) calculations. The proposed TiO2-SnO2 sensor displayed an ultrasensitive response for detecting acetone vapors which is almost 12 times and a limit of detection of 0.02 ppm. DFT calculations showed that the adsorption of acetone gas on (110) and (101) facets is thermodynamically favorable. Moreover, TiO2-SnO2 heterostructures sensor displayed high gas response, selectivity, repeatability, and long-term stability. The developed sensor also demonstrated excellent resistance against humidity due to a good synergy between the component oxides, band bending, availability of chemisorbed oxygen, and adsorption-desorption mechanism at the TiO2-SnO2 heterojunction. This work provides a foundation for the development of advanced gas sensors for hazardous sensing of materials exposed to diabetic patients in the human environment.