Despite evidence linking prenatal acetaminophen (APAP) exposure and adverse neurodevelopment in humans and animals, over half of pregnant women in most populations use APAP. Prior studies could be biased by inaccurate self-reported APAP use, and the molecular mechanisms linking prenatal APAP with adverse neurodevelopment are unknown. We estimated associations between maternal plasma biomarkers of APAP exposure, child attention deficit hyperactivity disorder (ADHD), and placental gene expression in 307 African-American mother-child pairs. Overall, detection of APAP in 2nd trimester plasma was associated with higher odds for child ADHD diagnosis (Odds Ratio (OR)=3.15 [95%CI: 1.20-8.29]). Prenatal APAP exposure and ADHD were associated with placental upregulation of immune system pathways in females, and downregulation of oxidative phosphorylation in both sexes. In females only, prenatal APAP was associated with 5.22% higher odds (0.0456%-13.1%) of ADHD statistically mediated through increased immunoglobulin heavy constant gamma 1 (IGHG1) expression. These results highlight placental molecular mechanisms that may underlie developmental toxicity of prenatal APAP exposure.