Ammonia could be regarded as one detrimental pollutant with an acrid smell in livestock sheds. So far, the pig breeding industry became the main source of atmospheric ammonia. Previous literature demonstrated that excessive ammonia inhalation might cause a series of physiological damage to multiple organs. Unfortunately, the toxicity mechanisms of gaseous ammonia to the porcine nervous system need further research to elucidate. Selenium (Se) involves in many essential physiological processes and has a mitigative effect on the exogenous toxicant. There were scant references that corroborated whether organic Se could intervene in the underlying toxicity of ammonia to the hypothalamus. In the present study, multi-omics tools, ethology, and molecular biological techniques were performed to clarify the detailed mechanisms of relaxation effects of L-selenomethionine on ammonia poisoning. Our results showed that ammonia inhalation caused the clinical symptoms and the increment of positive apoptosis rate in the hypothalamus with the dysfunction of mitochondrial dynamics factors, while obvious mitochondria structure defects were observed. In parallel, the inflammation medium levels and gut microbes-driven metabolism function were altered to mediate the neurotoxicity in fattening pigs through the initiation of inflammation development. Interestingly, L-selenomethionine could attenuate ammonia toxicity by activating the PI3K/Akt/PPAR-γ pathway to inhibit the mitochondria-mediated apoptosis process, blocking the abnormal immune response and the accumulation of reactive oxygen species in the nucleus. Meanwhile, Se could enhance the production performance of fattening sows. Taken together, our study verified the novel hypothesis for the toxicity identification of aerial ammonia and provided a therapeutic strategy for the treatment of occupational poisoning.