Sulfur dioxide (SO2) pollution in atmospheric environment is involved in neurotoxicity and increased risk for hospitalization and mortality of many brain disorders; however, our understanding of the mechanisms by which SO2 caused harmful insults on neurons remains elusive. Here, we show that SO2 exposure produced a neuronal insult, and the neurotoxic effect was likely via stimulating cyclooxygenase-2 (COX-2) elevation by activation of nuclear factor-κB (NF-κB) activity and its acting on the promoter-distal NF-κB–binding site of COX-2 promoter. The action of SO2 on elevating COX-2 ultimately appeared to be dependent on the increased production of arachidonic acid–derived prostaglandins, mainly prostaglandin E2 (PGE2), and functioning of its EP2/4 receptors. Also, the molecular modulating process might be triggered by free radical attack from SO2 metabolism in vivo and followed by activating cyclic adenosine monophosphate/protein kinase A pathway and enhancing probability of the release of glutamate, upregulating N-methyl-D-aspartic acid receptor expression and causing neuronal apoptosis. Our results reveal a mechanistic basis for exploring an association between SO2 inhalation and increased risk for neurological disorders and opening up therapeutic approaches of treating, ameliorating, or preventing brain injuries resulting from SO2 exposure in atmospheric polluting environment.