To investigate neural mechanisms of local thermotherapy to reduce mental stress, participants were required to perform mental arithmetic after treatment by a heat- and steam-generating sheet on the facial eyelid region while hemodynamic activity and ECGs were monitored. The results indicated that thermotherapy decreased hemodynamic activity in the anterior dorsomedial prefrontal cortex (aDMPFC) involved in sympathetic activity. Consistently, thermotherapy increased parasympathetic activity while it decreased sympathetic activity. Furthermore, thermotherapy increased hemodynamic activity in the dorsolateral prefrontal cortex (DLPFC) during mental arithmetic. These hemodynamic responses in the DLPFC during mental arithmetic were negatively correlated with that in the aDMPFC during thermotherapy. The results suggest that thermotherapy in the facial eyelid region is useful to ameliorate mental fatigue through its effects on the prefrontal cortex.