BACKGROUND: Mindfulness-based stress reduction (MBSR) alleviates depression and anxiety in adults with autism spectrum disorder (ASD); however, underlying therapeutic neural mechanisms and mindfulness-specific effects have yet to be elucidated. METHODS: We randomly assigned adults with ASD to MBSR or social support/education (SE). They completed questionnaires that assessed depression, anxiety, mindfulness traits, autistic traits and executive functioning abilities as well as a self-reflection functional MRI task. We used repeated-measures analysis of covariance (ANCOVA) to evaluate behavioural changes. To identify task-specific connectivity changes, we performed a generalized psychophysiological interactions (gPPI) functional connectivity (FC) analysis on regions of interest (ROIs; insula, amygdala, cingulum and prefrontal cortex [PFC]). We used Pearson correlations to explore brain-behaviour relationships. RESULTS: Our final sample included 78 adults with ASD - 39 who received MBSR and 39 who received SE. Mindfulness-based stress reduction uniquely improved executive functioning abilities and increased mindfulness traits, whereas both MBSR and SE groups showed reductions in depression, anxiety and autistic traits. Decreases specific to MBSR in insula-thalamus FC were associated with anxiety reduction and increased mindfulness traits, including the trait "nonjudgment;" MBSR-specific decreases in PFC-posterior cingulate connectivity correlated with improved working memory. Both groups showed decreased amygdala-sensorimotor and medial-lateral PFC connectivity, which corresponded with reduced depression. LIMITATIONS: Larger sample sizes and neuropsychological evaluations are needed to replicate and extend these findings. CONCLUSION: Together, our findings suggest that MBSR and SE are similarly efficacious for depression, anxiety and autistic traits, whereas MBSR produced additional salutary effects related to executive functioning and mindfulness traits. Findings from gPPI identified shared and distinct therapeutic neural mechanisms, implicating the default mode and salience networks. Our results mark an early step toward the development of personalized medicine for psychiatric symptoms in ASD and offer novel neural targets for future neurostimulation research. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04017793.