AbstractIrisin is a glycosylated protein formed from the hydrolysis of fibronectin type III domain‐containing protein 5 (FNDC5). Recent studies have demonstrated that FNDC5/Irisin is involved in the regulation of glucose and lipid metabolism, it can inhibit inflammation and have neuroprotective effects. However, the effect and mechanism of FNDC5/Irisin on motor neuron‐like cell lines (NSC‐34) have not been reported. In this study, we used lipopolysaccharide to construct cellular oxidative stress injury models and investigated the potential roles of FNDC5/Irisin on neurons by different cellular and molecular pathways. Taken together, our findings showed that FNDC5/Irisin can protect neurons, and this effect might be associated with Caspase3 and Bax pathways. These results laid the foundation for neuronal protection and clinical translation of FNDC5/Irisin therapy.