. Post-COVID-19 condition refers to a range of persisting physical, neurocognitive, and neuropsychological symptoms after SARS-CoV-2 infection. The mechanism can be related to brain tissue pathology caused by virus invasion or indirectly by neuroinflammation and hypercoagulability. This randomized, sham-control, double blind trial evaluated the effect of hyperbaric oxygen therapy (HBOT or HBO2 therapy) on post-COVID-19 patients with ongoing symptoms for at least 3 months after confirmed infection. Seventy-three patients were randomized to receive daily 40 session of HBOT (n = 37) or sham (n = 36). Follow-up assessments were performed at baseline and 1–3 weeks after the last treatment session. Following HBOT, there was a significant group-by-time interaction in global cognitive function, attention and executive function (d = 0.495, p = 0.038; d = 0.477, p = 0.04 and d = 0.463, p = 0.05 respectively). Significant improvement was also demonstrated in the energy domain (d = 0.522, p = 0.029), sleep (d = − 0.48, p = 0.042), psychiatric symptoms (d = 0.636, p = 0.008), and pain interference (d = 0.737, p = 0.001). Clinical outcomes were associated with significant improvement in brain MRI perfusion and microstructural changes in the supramarginal gyrus, left supplementary motor area, right insula, left frontal precentral gyrus, right middle frontal gyrus, and superior corona radiate. These results indicate that HBOT can induce neuroplasticity and improve cognitive, psychiatric, fatigue, sleep and pain symptoms of patients suffering from post-COVID-19 condition. HBOT’s beneficial effect may be attributed to increased brain perfusion and neuroplasticity in regions associated with cognitive and emotional roles.Gustatory (GD) and olfactory (OD) dysfunctions are the most frequent neurological manifestations of COVID-19. We used mental imagery as an experimental psychological paradigm to access olfactory and gustatory brain representations in 80 Italian COVID-19 adult patients (68.75% reported both OD and GD). COVID-19 patients with OD + GD have a significantly and selectively decreased vividness of odor and taste imagery, indicating that COVID-19 has an effect on their chemosensory mental representations. OD + GD length and type influenced the status of mental chemosensory representations. OD + GD were become all COVID-19 negative at the time of testing. Data suggest that patients are not explicitly aware of long-term altered chemosensory processing. However, differences emerge when their chemosensory function is implicitly assessed using self-ratings. Among patients developing OD + GD, self-ratings of chemosensory function (taste, flavor) were significantly lower as compared to those who did not. At the level of mental representation, such differences can be further detected, in terms of a reduced ability to mentally activate an odor or taste mental image. Our study shows that COVID-19 infection not only frequently causes hyposmia and dysgeusia, but that may also alter the mental representations responsible for olfactory and gustatory perception.