Background: Adolescent and young adult cancer patients (AYACPs) experience a high incidence of psychological distress. However, the effect of psychological distress on the functional connectivity between the hemispheres in AYACPs remains unknown. Voxel-mirrored homotopy connectivity detection is an effective way to explore the effects of psychological distress on functional connectivity throughout the brain in AYACPs. Methods: Twenty-four AYACPs underwent structural magnetic resonance imaging. Results: Voxel-mirrored homotopy connectivity in the psychological distress group was significantly lower in the superior parietal gyrus, middle frontal gyrus (orbital part), superior frontal gyrus (dorsolateral), superior occipital gyrus, precuneus, lingual gyrus, calcarine fissure and surrounding cortex than in the non-psychological distress group, while in the inferior temporal gyrus and middle frontal gyrus (orbital part), voxel-mirrored homotopy connectivity was significantly higher (p 0.05). ROC curve analysis showed that the decrease in voxel-mirrored homotopy connectivity in the following brain regions was helpful in distinguishing the psychological distress group from the non-psychological distress group: left superior frontal gyrus (dorsolateral), left calcarine fissure and surrounding cortex, right postcentral gyrus, and left precuneus. Conclusions: Activity imbalances in multiple brain regions exist in AYACPs with psychological distress. Voxel-mirrored homotopy connectivity detection is an effective way to explore the potential neural mechanisms of mental disorders in AYACPs and optimize the treatment of mental disorders.