ObjectiveDespite the overwhelming evidence for profound and longstanding effects of early‐life stress (ELS) on inflammation, brain structure, and molecular aging, its impact on human brain aging and risk for neurodegenerative disease is poorly understood. We examined the impact of ELS severity in interaction with age on blood‐based markers of neuroinflammation and neurodegeneration, brain volumes, and cognitive function in middle‐aged women.MethodsWe recruited 179 women (aged 30–60 years) with and without ELS exposure before the onset of puberty. Using Simoa technology, we assessed blood‐based markers of neuroinflammation and neurodegeneration, including serum concentrations of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL). We further obtained T1‐weighted and T2‐weighted magnetic resonance images to assess brain volumes and we assessed cognitive performance sensitive to early impairments associated with the development of dementia, using the Cambridge Neuropsychological Automated Test Battery. We used generalized additive models to examine nonlinear interaction effects of ELS severity and age on these outcomes.ResultsAnalyses revealed significant nonlinear interaction effects of ELS severity and age on NfL and GFAP serum concentrations, total and subcortical gray matter volume loss, increased third ventricular volume, and cognitive impairment.InterpretationThese findings suggest that ELS profoundly exacerbates peripheral, neurostructural, and cognitive markers of brain aging. Our results are critical for the development of novel early prevention strategies that target the impact of developmental stress on the brain to mitigate aging‐related neurological diseases. ANN NEUROL 2025;97:642–656