Objectives The mechanism of orthodontic pain modulation with a placebo remains largely unknown. This study aimed to investigate the placebo modulation of brain activity associated with orthodontic pain using functional magnetic resonance imaging (fMRI). Methods This longitudinal fMRI experiment recruited 23 volunteers and a self-contrast method was used. At first time, the participants were scanned without placebo (first period), followed by a 30-day washout, the participants were scanned again with placebo administration (second period). Orthodontic pain was caused by orthodontic separators placement between the lower right molars for both two periods. 24 h after placement, the MRI scans were taken, including a bite/non-bite task fMRI and a resting-state fMRI. A generalized linear model was used to identify pain-regulating network from task fMRI. Functional connectivity analysis of pain-related brain regions was performed to study the placebo effect on connectivity of pain-regulating networks using resting-state fMRI. Results The results of brain activation patterns were largely similar under placebo and non-placebo conditions. Under the non-placebo condition, the activities in multiple brain regions, including the pre-central gyrus, superior frontal gyrus, superior parietal lobule, and supramarginal gyrus, were significantly higher than that of the placebo condition. However, the anterior cingulate cortex (ACC) was activated under the non-placebo condition but not in the placebo one. The functional connectivities between ACC and orbitofrontal cortex, and the dorsolateral prefrontal cortex and orbitofrontal cortex were reduced under placebo condition. Conclusion Participants demonstrated similar brain activation patterns for orthodontic pain with or without placebos. With placebo, reduced activation in primary sensory cortex and decreased activation in ACC indicated that ACC could be fundamental in analgesia.