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Pediatric cancer treatment, especially for brain tumors, can have profound and complicated late effects. With the survival rates increasing because of improved detection and treatment, a more comprehensive understanding of the impact of current treatments on neurocognitive function and brain structure is critically needed. A frontline medulloblastoma clinical trial (SJMB03) has collected data, including treatment, clinical, neuroimaging, and cognitive variables. Advanced methods for modeling and integrating these data are critically needed to understand the mediation pathway from the treatment through brain structure to neurocognitive outcomes. We propose an integrative Bayesian mediation analysis approach to model jointly a treatment exposure, a high‐dimensional structural neuroimaging mediator, and a neurocognitive outcome and to uncover the mediation pathway. The high‐dimensional imaging‐related coefficients are modeled via a binary Ising–Gaussian Markov random field prior (BI‐GMRF), addressing the sparsity, spatial dependency, and smoothness and increasing the power to detect brain regions with mediation effects. Numerical simulations demonstrate the estimation accuracy, power, and robustness. For the SJMB03 study, the BI‐GMRF method has identified white matter microstructure that is damaged by cancer‐directed treatment and impacts late neurocognitive outcomes. The results provide guidance on improving treatment planning to minimize long‐term cognitive sequela for pediatric brain tumor patients. [ABSTRACT FROM AUTHOR]