Objective. In the last few years, the interest in applying virtual reality systems for neurorehabilitation is increasing. Their compatibility with neuroimaging techniques, such as functional near-infrared spectroscopy (fNIRS), allows for the investigation of brain reorganization with multimodal stimulation and real-time control of the changes occurring in brain activity. The present study was aimed at testing a novel semi-immersive visuo-motor task (VMT), which has the features of being adopted in the field of neurorehabilitation of the upper limb motor function. Approach. A virtual environment was simulated through a three-dimensional hand-sensing device (the LEAP Motion Controller), and the concomitant VMT-related prefrontal cortex (PFC) response was monitored non-invasively by fNIRS. Upon the VMT, performed at three different levels of difficulty, it was hypothesized that the PFC would be activated with an expected greater level of activation in the ventrolateral PFC (VLPFC), given its involvement in the motor action planning and in the allocation of the attentional resources to generate goals from current contexts. Twenty-one subjects were asked to move their right hand/forearm with the purpose of guiding a virtual sphere over a virtual path. A twenty-channel fNIRS system was employed for measuring changes in PFC oxygenated-deoxygenated hemoglobin (O2Hb/HHb, respectively). Main results. A VLPFC O2Hb increase and a concomitant HHb decrease were observed during the VMT performance, without any difference in relation to the task difficulty. Significance. The present study has revealed a particular involvement of the VLPFC in the execution of the novel proposed semi-immersive VMT adoptable in the neurorehabilitation field.