Mercuric chloride (HgCl 2 ), a heavy metal compound, causes neurotoxicity of animals and humans. Selenium (Se) antagonizes heavy metal-induced organ damage with the properties of anti-oxidation and anti-inflammation. Nevertheless, the molecular mechanism underlying the protective effects of sodium selenite (Na 2 SeO 3 ) against HgCl 2 -induced neurotoxicity remains obscure. Therefore, the present study aimed to explore the protective mechanism of Na 2 SeO 3 on HgCl 2 -induced brain damage in chickens. Morphological observations showed that Na 2 SeO 3 alleviated HgCl 2 -induced brain tissues damage . The results also showed that Na 2 SeO 3 decreased the protein expression of S100 calcium binding protein B (S100B), and increased the levels of nerve growth factors (NGF), doublecortin domain containing 2 (DCDC2), as well as neurotransmitter to reverse HgCl 2 -induced brain dysfunction . Further, Na 2 SeO 3 attenuated HgCl 2 -induced oxidative stress by decreasing the level of malondialdehyde (MDA) and increasing the activities of total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC). Mechanistically, Na 2 SeO 3 activated the brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase receptor type B (TrKB)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and suppressed the nuclear factor kappa B (NF-κB) signaling pathway to inhibit apoptosis and inflammation caused by HgCl 2 exposure. In summary, Na 2 SeO 3 ameliorated HgCl 2 -induced brain injury via inhibiting apoptosis and inflammation through activating BDNF/TrKB/PI3K/AKT and suppressing NF-κB pathways.