Importance Adverse prenatal exposures (APEs) often co-occur and independently associate with risk for childhood psychopathology. Whether exposure to multiple APEs is associated with persistent clinical effects through adolescence or underlying changes in brain maturation remains uncertain. Objective To evaluate longitudinal associations among cumulative APE burden, risk for psychopathology, and age-related cortical thinning in adolescents. Design, Setting, and Participants This cohort study analyzed 4-year follow-up data from the Adolescent Brain Cognitive Development (ABCD) Study, which enrolled 11 868 youth aged 9 to 10 years beginning in 2016. Sibling-comparison analysis was performed on 414 nonadopted sibling pairs with discordant APEs. Statistical analysis occurred from March to September 2025. Exposures Cumulative APE burden was calculated by summing 6 binary prenatal exposures that independently associated with psychopathology at baseline: unplanned pregnancy; early maternal prenatal alcohol, tobacco, or marijuana use; complicated pregnancy; and complicated birth. Main Outcomes and Measures Outcomes included annual Child Behavior Checklist (CBCL) scores of dimensional psychopathology, using both continuous and thresholded outcomes and biennial cortical thickness measures from structural magnetic resonance imaging, analyzed using linear mixed-effects models. Results Of 8515 singleton children (mean [SD] baseline age, 9.9 [0.6] years; 4460 male [52.4%]), 6644 (78%) were exposed to at least 1 APE. Multiple APEs persistently and dose-dependently associated with increased odds of clinically significant psychopathology (CBCL total problems: exposure to 1 APE [odds ratio (OR), 2.01; 95% CI, 1.28-3.16; corrected P = .006], 2 APEs [OR, 3.82; 95% CI, 2.39-6.11; corrected P &lt;.001], and 3 or more APEs [OR, 6.75; 95% CI, 4.14-11.02; corrected P &lt;.001]). Associations of APEs with attention-deficit/hyperactivity disorder symptoms attenuated over time (interaction: F = 13.51; corrected P = 7.13 × 10 −8 ), whereas those with depressive symptoms potentiated (interaction: F = 5.82; corrected P = .002). Greater APE burden associated with accelerated age-related cortical thinning in 36 of 68 cortical regions (interaction for the right middle temporal cortex: F = 8.89; corrected P &lt; .001). Siblings with more exposures demonstrated persistently higher CBCL total problems ( t = 2.25; P = .03) and accelerated cortical thinning in 5 of the 36 regions implicated in the larger sample. Conclusions and Relevance Results of this cohort study show that multiple prenatal adversities were associated with altered developmental trajectories of psychopathology and cortical maturation into midadolescence. These findings highlight the importance of fetal programming to mental health across life course and the need for additional study of risk and resiliency-conferring factors in utero.