Polybrominated diphenyl ethers (PBDEs) are synthetic halogen compounds, industrially used as flame retardants in many flammable products. PBDEs are environmentally persistent and bioaccumulative substances that were used from the 1970s and discontinued in the 1990s. PBDEs are present in air, soil, water, and food, where they remain stable for a long time. Chronic exposure to PBDEs is associated with adverse human health effects, including cancer, immunotoxicity, hepatotoxicity, reproductive and metabolic disorders, motor and hormonal impairments, and neurotoxicity, especially in children. It has been demonstrated that PBDE exposure can cause mitochondrial and DNA damage, apoptosis, oxidative stress, epigenetic modifications, and changes in calcium and neurotransmitter levels. Here, we conduct a comprehensive review of the molecular mechanisms of the neurotoxicity of PBDEs using different approaches. We discuss the main neurotransmitter pathways affected by exposure to PBDEs in vitro and in vivo in different mammalian models. Excitatory and inhibitory signaling pathways are the putative target where PBDEs carry out their neurotoxicity. Based on this evidence, environmental PBDEs are considered a risk to human public health and a hazard to biota, underscoring the need for environmental monitoring to mitigate exposure to PBDEs.