Background:Cognitive impairment is common among adolescent and young adult (AYA) cancer survivors. Physical activity (PA) may help mitigate cognitive impairment post-treatment by positively impacting two indicators of general brain health: fractional anisotropy (FA) and functional connectivity (FC). As part of a two-arm, mixed-methods pilot randomized controlled trial (RCT), this sub-study was designed to provide preliminary proof-of-concept evidence for the effects of PA on FA and FC among AYA cancer survivors post-treatment to help inform decisions about proceeding to larger trials.Methods:AYA cancer survivors who had completed cancer treatment and who were enrolled in a larger pilot RCT comparing a 12-week PA intervention to a waitlist control group, were invited to participate in this sub-study. Sub-study participants completed diffusion tensor imaging and resting-state functional magnetic resonance imaging prior to randomization and post-intervention. Data were analyzed with descriptive statistics, independent component analysis, and paired sample t-tests.Results:Post-intervention, participants showed increases in FA of the bilateral hippocampal cingulum, left anterior corona radiata, middle cingulum, left anterior thalamic radiation, and left cerebellum. A decrease in overall FC of the default mode network and increases in the cerebellar and visual networks were also noted post-intervention (p < .05).Conclusion:Results provide preliminary evidence for the possible positive effects of PA on FA and FC among AYA cancer survivors post-treatment. On the basis of these results, larger trials assessing the effects of PA on specific brain health indicators, as captured by FA and FC, among AYA cancer survivors are appropriate and warranted.