Tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) possesses potent anti-inflammatory effect. However, if TIPE2 ameliorates sciatic nerve injury (SNI)-induced inflammation and pain remains undiscussed, and the underlying role TAK1 in it were unknown. To verify our imagine, we performed SNI surgery, and analyzed expression and colocalization of TIPE2 and TAK1 in spinal cord and dorsal root neurons (DRG) by immunofluorescence staining and western blot. And the biological analysis, inflammatory factors, and pathological improvement were determined, and the regulation of TIPE2 in TAK1, phosphor-NF-κB, phospho-JNK was also tested by immunofluorescence staining and western blot. Experimental results showed the parabola-like change of TIPE2 and rising expression of TAK1 in spinal cord and DRG. And intrathecal TIPE2 injection could significantly improve the status of SNI rats, inhibit level of IL-6, IL-10 and TNF-α, raise the thermal withdrawal relax latency and mechanical withdrawal thresholds. Meanwhile, we also detected how TIPE2 regulated TAK1, and the downstream pathway NF-κB and JNK. The result indicated that TIPE2 could reduce TAK1 expression, and make NF-κB and JNK inactivated. To deeply discuss the potential mechanism, we injected TAK1 oligodeoxynucleotide into rats, and found that TIPE2 exerted the protective role against SNI through TAK1. In brief, TIPE2 reduced expression of TAK1, thereby inhibiting activation of NF-kB and JNK, further improving the neuroinflammation and neuropathic pain. TIPE2 played a protective role in sciatic nerve injury rats through regulating TAK1.