Acute spinal cord injury (SCI) is one of the serious central nervous system injuries, which can lead to significant neurological impairments and a reduction in quality of life with loss in sensory and motor functions. Although recent advancements contribute to the understanding of the underlying pathophysiological processes developed after SCI, currently, there is limited innovative and effective treatment options besides conventional rehabilitation and management of SCI to alleviate the condition. Improvements in neurological functions of the individuals with SCI depend mainly on the mechanical damage occurring in the primary injury and on pathophysiological alterations associated with secondary damage. Since in the treatment of SCI, there are no therapeutic strategies for neurological alterations caused by primary injury, all innovative treatments utilize treatment strategies targeting to the secondary damage. Non-steroidal anti-inflammatory drugs (NSAIDs) have become the focus of various experimental SCI models as these may be expected to reduce inflammation in secondary damage due to their potent anti-inflammatory effects. Experimentally, they exhibit neuro-protective and apoptotic effects by suppressing axonal re-growth, thus inhibiting the RhoA pathway, which leads to apoptotic cell death, in addition to the recovery of motor functions along with histological improvement. However, histological improvement is not significantly associated with improvement of motor function. The main target of SCI research should not only focus on histological improvement of lesion, but also on its potential for contribution to effective clinical therapies targeting improvements in sensory and motor functions. In the present review, we have summarized the current knowledge about pathophysiologic mechanisms working after SCI and discussed the potential of NSAIDs as promising agents in the management of SCI.