Spinal cord injury (SCI) is a chronic disease causing motor and sensory loss in the affected individuals. The SCI has a huge impact on the lives of patients that makes them susceptible to life-long disability. However, the current clinical modalities are ineffective to cope the aftermath of SCI. Thus, in the present study, we aimed to develop a series of 1,3,5-triazine derivatives as a protective agent against SCI. The molecules were developed by facile synthetic route and obtained in excellent yield. The compounds were tested for their efficacy to inhibit the transcription of NF-κB in RAW 264.7 cells, where they displayed mild to potent activity. Compound 8a was identified as most potent NF-κB inhibitor among the tested analogues. The effect of compound 8a was further scrutinized against the SCI injury in rats induced by contusion injury. It has been found that compound 8a improves motor function of rats together with reduction in inflammation and edema in spinal cord of rats. It also showed to inhibit oxidative stress and inflammation in the SCI rats. In a western blot analysis, after SCI induction, compound 8a inhibited NF-κB and its upstream regulator TLR4 in a dose-dependent manner. Collectively, our study provides a novel class of agent that provide protective action against SCI.