Brominated flame retardants are widely used chemicals that induce a myriad of neurotoxic effects, all of which are not well understood. Although many flame retardants have since been banned, their environmental persistence results in ongoing, population-level exposure. A thorough understanding of the neurotoxic effects across different brain regions and organs is therefore needed. Here, we find that brominated flame retardants of various types demonstrate distinct hippocampal neurotoxicity in vitro, inducing time and chemical-dependent effects on hippocampal neural cells. Further evaluation indicated that autophagy or autophagic defects could be a common mechanism of hippocampal neurotoxicity across different flame retardants. Upon subchronic in vivo HBCD exposure, highly region-dependent effects were observed on the brain transcriptome, with far greater effects on the dorsal striatum and frontal cortex than the hippocampus. These changes predominantly correlated with highly lipid-rich cellular components. In fact, further study demonstrates that hexabromocyclododecane (HBCD) exposure induces changes in lipid composition within the brain, liver and blood. HBCD exposure was also found to induce changes in the cecal microbiome, potentially in part explaining some of the changes in the brain lipidome. Taken together, the data support the hypothesis that flame retardants induce differential neurotoxicity across different subcompartments of the brain, which may be related to lipid changes. These studies provide an important basis for future study on the mechanisms by which flame retardants induce differential toxic effects on the brain. Such studies will significantly advance our ability to accurately perform risk assessments for BFR exposures and facilitate safer BFR design.