Objectives The aim of the present work was to determine the functional role of the TLR signaling cascade in P0106-125-induced murine experimental autoimmune neuritis (EAN). Therefore, we have addressed the specific impact of TLR2 and TLR4 as well as their associated adaptor proteins MyD88 and TRIF on EAN. Methods In TLR20/0, TLR40/0, MyD880/0, and TRIF0/0 mice as well as in co-isogenic C57BL/6J mice, which served as controls, P0106-125-induced murine EAN was established. Disease prevalence and activity were determined according to a well-established score. Animals were sacrificed at indicated time points to obtain the organ samples and blood samples for further analyses: histopathology, flow cytometry, immunoassays, qRT-PCR and Western Blot. Results Imm. TLR20/0, imm. TLR40/0, imm. MyD880/0, and imm. TRIF0/0 mice, respectively, revealed significantly attenuated disease activity and mild neuritis development as compared to imm. C57BL/6 control mice. Decreased systemic levels of the pro-inflammatory cytokines IL-6, IL-12p40, and IL-17A determined in the spleens of mutant strains were the result of an impaired NF-κB activation. Prolonged recoveryobserved in TLR2-deficient mice was associated with an impaired shift of macrophages from the M1 towards the M2 phenotype, impaired Tregs development as well as an attenuated differentiation of Th2 helper cells. Conclusion The present data emphasize the functional importance of TLR2, TLR4, MyD88, and TRIF molecules in murine model of autoimmune neuritis, marking them as important modulators in the immune network. Beside, these results shed new lights on potentially novel, promising therapeutic strategies for patients with the acute axonal form of Guillain-Barré syndrome.