© 2019 The Author(s) Over the past few years, the number of Japanese astronauts recruited for a long-term stay in the International Space Station (ISS) has increased. However, no consensus has been reached on a standardized method for measuring psychosocial stress triggered under such confined environment conditions, and on methods to effectively minimize the detrimental effects of such stress. To address this matter, we aimed to inspect stress-related index measurements of frontal brain function in experiments simulating long-term space confinement environment at the Japan Aerospace Exploration Agency (JAXA). Study participants (N = 8, all adult men) were confined in the “confinement environment adaptation training facilities” of the Tsukuba Space Centre for 15 days, in a controlled, confined environment that attempted to closely simulate the conditions experienced by astronauts during the astronaut selection examination and inside the ISS. Frontal brain activation of the prefrontal cortex during a verbal fluency test (VFT) was evaluated as a confinement-related stress index, measured by functional near-infrared spectroscopy (fNIRS), a non-invasive brain-imaging method. An exercise intervention was additionally applied, using a single-case experimental ABA design (Intervention period (B): 5 days, 15 min aerobike daily exercise; Control periods (A): 5 days before and 5 days after intervention period, prohibition of any type of exercise), to observe whether exercise could have an ameliorating effect on the confinement-induced stress. The fNIRS values showed a significant decrease at the beginning of confinement when compared with the before-confinement values, remaining stable during confinement and thus showing no difference between the exercise intervention and control periods, ultimately returning to pre-confinement levels a week after confinement (analyzed using a generalized linear mixed model). The fNIRS-measured initial decrease in prefrontal cortex activity indicates that fNIRS can efficiently detect the confinement-triggered stress. Importantly, the stable fNIRS values during confinement suggest that exercise can maintain the frontal brain function assisting against further deterioration under confinement environment stress. Our results support that exercise can facilitate better prefrontal cortex activity combating the negative effects of confinement-induced stress, and therefore should be beneficial for maintaining good frontal brain function among astronauts in the ISS.