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Aims Irisin is a newly discovered actin that has been shown to be effective against inflammation-related symptoms. The aim of this study was to investigate the influence of Irisin on LPS-induced inflammation in vitro and to investigate the role of the mitogen-activated protein kinase (MAPK) pathway in the protecting effect of Irisin in LPS-stimulated RAW 264.7 macrophages.Methods Cell viability was assessed using MTT assay and flow cytometry, cell morphology was measured by optical microscope, IL-12 and IL-23 were detected by Elisa, and the levels of related proteins were analyzed by western blot. Phagocytosis of zymosan and clearance of apoptotic cells were measured.Results MTT assay and flow cytometry results showed that LPS-induced cytotoxicity was reversed by Irisin(p<0.001), after coincubation with Irisin, the level of IL-12 and IL-23 decreased in LPS-stimulated RAW264.7 macrophages(p>0.05). Irisin pretreatment significantly inhibited the phosphorylation of ERK and AKT and increased the expression of PPAR α and PPAR γ(p<0.05). LPS-induced enhancement of phagocytosis(p<0.05) and cell clearance was reversed by Irisin pretreatment(p<0.001).Conclusions Irisin ameliorated LPS-induced inflammation by inhibiting cytotoxicity and apoptosis, and this protective effect may be mediated through the MAPK pathway.