Volatile organic compounds (VOCs) detection is in high demand for clinic treatment, environment monitoring, and food quality control. Especially, VOCs from human exhaled breath can serve as significant biomarkers of some diseases, such as lung cancer and diabetes. In this study, a smartphone-based sensing system was developed for real-time VOCs monitoring using alternative current (AC) impedance measurement. The interdigital electrodes modified with zinc oxide (ZnO), graphene, and nitrocellulose were used as sensors to produce impedance responses to VOCs. The responses could be detected by a hand-held device, sent out to a smartphone by Bluetooth, and reported with concentration on an android program of the smartphone. The smartphone-based system was demonstrated to detect acetone at concentrations as low as 1.56 ppm, while AC impedance spectroscopy was used to distinguish acetone from other VOCs. Finally, measurements of the exhalations from human being were carried out to obtain the concentration of acetone in exhaled breath before and after exercise. The results proved that the smartphone-based system could be applied on the detection of VOCs in real settings for healthcare diagnosis. Thus, the smartphone-based system for VOCs detection provided a convenient, portable and efficient approach to monitor VOCs in exhaled breath and possibly allowed for early diagnosis of some diseases.