Neuropathic pain is a complex, debilitating disease that results from injury to the somatosensory nervous system. The presence of systemic chronic inflammation has been observed in chronic pain patients, but whether it plays a causative role remains unclear. This study aims to determine the perturbation of systemic homeostasis by an injury to peripheral nerve and its involvement in neuropathic pain. We assessed the proteomic profile in the serum of mice at one-day and one-month following partial sciatic nerve injury (PSNL) or sham surgery. We also assessed mouse mechanical and cold sensitivity in naive mice after receiving intravenous administration of serum from PSNL or sham mice. Mass spectrometry-based proteomic analysis revealed that PSNL resulted in a long-lasting alteration of serum proteome, where the majority of differentially expressed proteins were in inflammation related pathways, involving cytokines/chemokines, autoantibodies and complement factors. While transferring sham serum to naive mice did not change their pain sensitivity, PSNL serum significantly lowered mechanical thresholds and induced cold hypersensitivity in naive mice. With broad anti-inflammatory properties, bone marrow cell extracts (BMCE) not only partially restored serum proteomic homeostasis, but also significantly ameliorated PSNL-induced mechanical allodynia, and serum from BMCE-treated PSNL mice no longer induced hypersensitivity in naive mice. These findings clearly demonstrate that nerve injury has a long-lasting impact on systemic homeostasis, and nerve injury associated systemic inflammation contributes to the development of neuropathic pain.