Acupuncture is a commonly used therapy for treating functional dyspepsia (FD), although the mechanism remains unclear. The objectives of this study were to investigate the differences in cerebral glycometabolism changes evoked by acupuncture and sham acupuncture and to explore the possible correlations between brain responses and clinical efficacy. In all, 72 FD patients were randomly assigned to receive either acupuncture or sham acupuncture treatment for 4 weeks. Ten patients in each group were randomly selected for fluorine-18 fluorodeoxyglucose positron emission tomography computed tomography scans to detect cerebral glycometabolism changes. The Nepean Dyspepsia Index (NDI) and Symptom Index of Dyspepsia (SID) were used to evaluate the therapeutic effect. (i) The clinical data showed that after treatment the decrease in SID score in the acupuncture group was significantly greater than that in the sham acupuncture group (P<0.05). The increase in NDI score between the two groups did not differ (P>0.05), and only the improvement in NDI score in the acupuncture group was clinically significant. (ii) The neuroimaging data indicated that after treatment the acupuncture group showed extensive deactivation in cerebral activities compared with the sham acupuncture group. In the acupuncture group, the deactivations of the brainstem, anterior cingulate cortex (ACC), insula, thalamus, and hypothalamus were nearly all related to the decrease in SID score and the increase in NDI score (P<0.05, corrected). In the sham acupuncture group, the deactivations of the brainstem and thalamus tended to be associated with the increase in NDI score (P<0.1, corrected). Acupuncture and sham acupuncture have relatively different clinical efficacy and brain responses. Acupuncture treatment more significantly improves the symptoms and quality of life of FD patients. The more remarkable modulation on the homeostatic afferent network, including the insula, ACC, and hypothalamus, might be the specific mechanism of acupuncture.