Foot reflexology is a treatment with the hypothesis that such massage stimulation on the feet may cause a therapeutic effect which should be helpful for smoking cessation. However, its mechanism of action in the brain of smoking people remains unknown. Functional magnetic resonance imaging (fMRI) is helpful for real-time brain activity detection. We aim to compare the brain activity effects of foot reflexology with fMRI between smoking and nonsmoking subjects. We divided participants into experimental (smokers) and control groups (nonsmokers). Both groups received similar foot reflexology under the fMRI examination. Then, we compared the mean response score in each brain area before and after foot stimulation among groups and between groups. Five nonsmokers and fifteen smokers had completed the study. All participants were right-handed males, with a mean age of 38.6 years. The fMRI brain response in the areas correlated with foot stimulation, including the precentral gyrus of the frontal lobe and the postcentral gyrus of the parietal lobe, was present for all participants. The fMRI response outside the correlated area, including other parts of the frontal and parietal lobes, the temporal and occipital cortices, and the thalamus, was also found in all participants, but was not consistent. The fMRI of the brain is feasible and safe for demonstrating foot reflexology reactions. The response signal outside the correlated motor-sensory cortical area with foot reflexology may have clinical significance and may be helpful for smoking cessation. We suggest conducting a large-scale, randomized controlled trial to confirm these findings.