The prefrontal cortex (PFC) is involved in movement execution, sensory processing, cognition, memory, and learning. Notably, chewing-related PFC activity is not fully understood in regard to its critical participation in orofacial sensorimotor functions. In the present study, we attempted to clarify the following aspects: 1) involvement of chewing-related activation of the PFC in movement execution and programming, and sensory processing, 2) effects of chewing imagery on PFC activation, 3) functional significance of oral sensory input on PFC activity, 4) efficacy of prosthodontic treatment for activating the prefrontal cortex, and 5) functional characteristics of chewing-related PFC activity in patients with psychiatric disorders and occlusal dysesthesia. Eleven adult subjects (10 healthy, 1 with a psychiatric disorder) participated in this study. Near-infrared spectroscopy (HITACHI Medical Co., ETG-100) was used to determine the hemoglobin concentration ([oxy-Hb]) in the PFC. The task utilized was chewing gum (Lotte Co., Freezone), which was composed of 5 chewing trials, each conducted for 10 seconds. Deafferentation of oral sensory input was performed by applying lidocaine anesthesia into the unilateral inferior alveolar nerve. Our results for the five studied aspects are as follows. 1) Chewing-related PFC activity was indicated in the middle part of the dorsal PFC. 2) Chewing imagery activated the bilateral middle part of the dorsal PFC. 3) The right hemisphere was predominantly decreased in the post-anesthesia condition as compared with pre-anesthesia. 4) PFC activation was clearly initiated by wearing a partial denture prosthesis. 5) Chewing-related PFC activities in the subject with a psychiatric disorder showed a lower level of activation than in the healthy subjects. It is considered that the middle part of the dorsal PFC is involved in movement planning and execution, oral somatosensory processing, and sensorimotor integration in regard to chewing performance. Wearing a partial denture prosthesis activates the PFC, which might help to prevent cognitive and memory impairments in elderly individuals. Furthermore, patients with psychiatric disorders and persistent occlusal dysesthesia indicate that hypofrontality might be related to cognitive disruption of oral somatosensory input .