Thrombospondin 2 (THBS2), belongs to the platelet reactive protein family. It is a disulfide-linked homotrimeric glycoprotein that mediates cell-cell and cell-matrix interactions. Recently, a sequencing study suggested that THBS2 may be involved in the progression of spinal cord injury (SCI). This study aims to explore the expression pattern and the possible role of THBS2 in SCI, and the signaling pathway that THBS2 mainly relies on for its function. In the present study, we collected clinical samples and established both a rat model and a cell model of SCI. The expression of THBS2 in the model and clinical samples was detected by western blot assay/immunofluorescence and RT-qPCR. After establishing the rat SCI model, Basso-Beattie-Bresnahan (BBB) behavioral scores were used to detect changes in motor function. Spinal cord water content measurement was used to assess spinal cord edema in rats. To investigate the effect of THBS2 on SCI models, THBS2- expressing plasmid/THBS2-siRNA/SB 202190 (p38MAPK pathway inhibitor)/p38 agonist was applied to the rat SCI models and PC12 cell SCI model. Hematoxylin-eosin (H&E) staining was used to detect spinal cord lesions in rats. TUNEL and flow cytometry (FCM) assays were conducted to determine the apoptosis level, both in vivo and in vitro. Cell viability was determined by CCK-8 assay. Changes in inflammatory factor (TNF-α, IL-1β and IL-6) levels in models were quantified by enzyme linked immunosorbent assay (ELISA). Finally, p38MAPK signaling pathway-related proteins and apoptosis-related proteins were detected by western blot assay. The expression of THBS2 showed a gradual increase and decrease process after SCI, with the most significant increase observed in the mid-phase of SCI. THBS2-expressing plasmid and SB 202190 significantly increased BBB score scores, while decreased spinal cord water content. Also, the H&E staining results suggested that overexpression of THBS2-plasmid and SB 202190 could inhibit spinal cord lesions. THBS2 and SB 202190 treatment significantly enhanced the cell ability of LPS-induced PC12 cells. In addition, THBS2-expressing plasmid and SB 202190 inhibited the level of apoptosis and suppressed the secretion of inflammatory factors in both in vivo and in vitro models. Moreover, overexpression of THBS2 inhibited the activation of the p38MAPK signaling pathway in SCI models, and p38 agonist reversed the protective effects of THBS2-plasmid on SCI rats and LPS-induced PC12 cells. In addition, THBS2 down-regulation further promote LPS-induced apoptosis and inflammatory response in PC12 cells. THBS2 was highly expressed in SCI, and overexpression of THBS inhibited the activation of the MAPK signaling pathway and thus protects against SCI.