Several environmental pollutants have been shown to damage brain and affect gut microbiota. Limited evidence is available about the impact of “chemical cocktails” (CC) of xenobiotics on brain metabolome and their possible influence in the gut-brain crosstalk. To this end, BALB/c mice were exposed to heavy metals (As, Hg, Cd) and pharmaceuticals (diclofenac and flumequine) under regular rodent diet or supplemented with selenium (Se). Selenium, an antioxidant well-known for its antagonism against the neurotoxicity of several pollutants, modulated several brain metabolic impairments caused by CC (e.g., brain levels of the excitatory amino acid N-acetyl aspartic acid) by influencing mainly the metabolisms of purine, glycosylate and dicarboxylate, glutamate, glycerophospholipid, alanine and aspartate. Numerous associations were obtained between brain metabolites and gut microbes and they changed after Se-supplementation (e.g., Lactobacillus was positively associated with a brain ceramide, phosphoserine, phosphocholine, vitamin D3 derivative, fatty acids, malic acid, amino acids, and urea after the exposure, but not after Se-supplementation). Our results showed numerous evidences about the impact of CC on brain metabolome, the potential role of Se as an antagonist and their impact on the gut-brain axis. Further research is needed to understand the complex mechanism of action implied on CC-brain-microbiota interactions.