<p>Per- and polyfluoroalkyl substances (PFAS), a group of persistent organic pollutants characterized by C-F bonds, have been detected in various human samples and tend to accumulate in the brain, posing potential neurotoxic risks. Gaining insights into PFAS-induced neurotoxicity and its underlying molecular mechanisms is crucial for assessing health risks associated with human exposure, however, research in this area remains limited. This review summarizes studies on the processes of PFAS uptake, accumulation, and mechanisms within the brain: disruption of the blood–brain barrier (BBB) via tight junction interference and reliance on transporter proteins located at the BBB. Accumulation of PFAS in the brain has been linked to neurotoxic effects in the central nervous system (CNS), including attention-deficit/hyperactivity disorder (ADHD) in children and Parkinson’s or Alzheimer’s disease in older adults. Mechanistic investigations into neurotoxicity have focused on alterations in neurotransmitter levels, mitochondrial dysfunction, neuronal damage, and thyroid hormone signaling pathways. This study offers foundational support for a broader understanding of adverse neurological toxicity, mechanisms of brain penetration, and increased risks of behavioral and cognitive disorders due to PFAS exposure in humans.</p> Graphical Abstract <p></p>