The protective effect of Lactobacillus plantarum CCFM436 (L. plantarum CCFM436) against acute Mn toxicity was studied in mice based on an evaluation of its administration as a therapy or as a prevention strategy. Viable and nonviable L. plantarum CCFM436 cells showed better Mn binding ability than the other 8 Lactobacillus strains. The levels of Mn in feces, liver, kidney, and brain suggested its potential for alleviating acute Mn toxicity in mice. With the administration of viable CCFM436, the content of malondialdehyde decreased, while glutathione, superoxide dismutase, and catalase activity increased in tissues, which were beneficial for reducing the hepatic, renal, and cerebral oxidative stress. The reduction of the levels of pro-inflammatory cytokines and amyloid beta and the increase of the expression of TJ proteins in brain tissue showed the protective effect against Mn toxicity. The study suggested that L. plantarum CCFM436 was effective against Mn toxicity and could be considered as a potential dietary therapeutic strategy against acute Mn toxicity.