Background: Chondroitinase ABC (cABC), due to its loosening impact on the extracellular matrix scaffold, has been used to enhance regeneration of injured axonal tracts after spinal cord injury (SCI). However, cABC thermal instability at physiological temperature has limited its clinical application. The disaccharide trehalose has been shown to increase the stability of cABC in body temperature. Therefore, the present study was conducted to assess the effect of combined trehalose and cABC on inflammation, lipid peroxidation and histopathological changes following SCI. Methods: Male Wistar rats were randomized into six groups (n=12) including sham, SCI, vehicle, trehalose, cABC and trehalose + cABC. In sham group, only laminectomy was performed. Other groups underwent laminectomy followed by contusion spinal cord injury. Twenty four hours after treatment, the level of IL-1β , Myeloperoxidase (MPO) and Malondialdehyde (MDA) were measured. Histopathological changes were also scored. Results: Spinal cord injury in rats resulted in severe trauma characterized by increase in inflammation, oxidative stress, neutrophils infiltration, hemorrhage, necrosis and edema. The levels of IL-1β , MDA and MPO were 260. 3± 16. 4 nmol/mg protein, 1. 2± 0. 06 mU/mg protein and 18. 9± 0. 7 pg/mg protein, respectively in the vehicle group. However, combined treatment with cABC and trehalose reduced the amount of these factors significantly to 142. 4± 17 nmol/mg protein, 0. 57± 0. 03 mU/mg protein and 13. 8± 0. 4 pg/mg protein, respectively (P<0. 05). In addition, treatment with cABC and trehalose improved histopathological alterations. Conclusions: The present data suggest that coadministration of trehalose and cABC exhibits neuroprotection effect through reducing inflammation and tissue injury events associated with SCI.