Human exhaled breath has been utilized to identify biomarkers for diseases such as diabetes and cancer. The existence of these illnesses is indicated by a rise in the level of acetone in the breath. The development of sensing devices capable of identifying the onset of lung cancer or diabetes is critical for the successful monitoring and treatment of these diseases. The goal of this research is to prepare a novel breath acetone sensor made of Ag NPs/V₂O₅ thin film/Au NPs by combining DC/RF sputtering and post-annealing as synthesis methods. The produced material was characterized using X-ray diffraction (XRD), UV-Vis, Raman, and atomic force microscopy (AFM). The results revealed that the sensitivity to 50 ppm acetone of the Ag NPs/V₂O₅ thin film/Au NPs sensor was 96%, which is nearly twice and four times greater than the sensitivity of Ag NPs/V₂O₅ and pristine V₂O₅, respectively. This increase in sensitivity can be attributed to the engineering of the depletion layer of V₂O₅ through the double activation of the V₂O₅ thin films with uniform distribution of Au and Ag NPs that have different work function values.