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Objective: This study used childhood cancer survivors as a novel model to study whether children who experience central nervous system (CNS) injury are at higher risk for neurocognitive impairment associated with subsequent late onset chronic health conditions (CHCs). Methods: Adult survivors of childhood cancer (n = 2,859, ≥10 years from diagnosis, ≥18 years old) completed a comprehensive neurocognitive battery and clinical examination. Neurocognitive impairment was defined as age‐adjusted z score < 10th percentile. Participants impaired on ≥3 tests had global impairment. CHCs were graded using the Common Terminology Criteria for Adverse Events v4.3 (grade 1, mild; 2, moderate; 3, severe/disabling; 4, life‐threatening) and were combined into a severity/burden score by frequency and grade (none/low, medium, high, and very high). A total of 1,598 survivors received CNS‐directed therapy including cranial radiation, intrathecal methotrexate, or neurosurgery. Logistic regression estimated the odds of neurocognitive impairment associated with severity/burden score and grade 2 to 4 conditions, stratified by CNS treatment. Results: CNS‐treated survivors performed worse than non–CNS‐treated survivors on all neurocognitive tests and were more likely to have global neurocognitive impairment (46.9% vs 35.3%, p < 0.001). After adjusting for demographic and treatment factors, there was a dose–response association between severity/burden score and global neurocognitive impairment, but only among CNS‐treated survivors (high odds ratio [OR] = 2.24, 95% confidence interval [CI] = 1.42–3.53; very high OR = 4.07, 95% CI = 2.30–7.17). Cardiovascular and pulmonary conditions were associated with processing speed, executive function, and memory impairments in CNS‐treated but not non–CNS‐treated survivors who were impacted by neurologic conditions. Interpretation: Reduced cognitive/brain reserve associated with CNS‐directed therapy during childhood may make survivors vulnerable to adverse cognitive effects of cardiopulmonary conditions during adulthood. ANN NEUROL 2021;89:534–545 [ABSTRACT FROM AUTHOR]