Aim Hyperbaric hyperoxia (HBO) is known to modulate aerobic metabolism, vasoreactivity and blood flow in the brain. Nevertheless, mechanisms underlying its therapeutic effects, especially in traumatic brain injury (TBI) and stroke patients, are debated. The present study aimed at investigating regional cerebral blood flow (rCBF) distribution during acute HBO exposure. Methods Regional cerebral blood flow response was investigated in seven healthy subjects exposed to either normobaric normoxia or HBO with ambient pressure/inspired oxygen pressure of 101/21 and 250/250 kPa respectively. After 40 min at the desired pressure, they were injected a perfusion tracer and subsequently underwent brain single photon emission computed tomography. rCBF distribution changes in the whole brain were assessed by Statistical Parametric Mapping. Results During HBO, an increased relative rCBF distribution was found in sensory‐motor, premotor, visual and posterior cingulate cortices as well as in superior frontal gyrus, middle/inferior temporal and angular gyrus and cerebellum, mainly in the dominant hemisphere. During normobaric normoxia, a higher 99mTc‐HMPAO distribution in the right insula and subcortical structures as well as in bilateral hippocampi and anterior cingulated cortex was found. Conclusions The present study firstly confirmed the rCBF distribution increase during HBO in sensory‐motor and visual cortices, and it showed for the first time a higher perfusion tracer distribution in areas encompassed in dorsal attention system and in default mode network. These findings unfold both the externally directed cognition performance improvement related to the HBO and the internally directed cognition states during resting‐state conditions, suggesting possible beneficial effects in TBI and stroke patients.