Spinal cord injury (SCI) and associated pain and inflammation caused by trauma or infection are serious health care issues world-wide. The various inflammatory, redox-sensitive and apoptotic events are contributing factors, but altered neuronal function, axonal degeneration, activated microglia, endothelial cells, astrocytes, fibroblasts, pericytes, Schwann cells, and meningeal cells are major players in its pathogenesis. Further, monocytes and neutrophil infiltration get recruited and facilitate the release of chemokines, cytokines, and other mediators of inflammation. This event leads to the production of different amino acids, neuropeptides kinin, prostaglandins, prostacyclin, thromboxane, leukotrienes, bradykinin, histamine, matrix metal proteinases, and serotonin that stimulate nerve endings and manifest the inflammation and pain processes, etc. Arachidonic acid (AA), NF-kB, NLRP3 inflammasome, and nitric oxide pathways along with P2X7 receptor and ion channel transient receptor potential (TRP) vanilloid are some of the recently explored targets for modulation of pain and inflammation in SCI. Till now, NSAIDs, opioids, antidepressants, anticonvulsants, NMDA antagonists, α2-adrenergic agonists, and GABA-receptor agonists are used for the management of these pathological conditions. However, these drugs are associated with various side effects. Additionally, the number of available animal models for SCI has enhanced the understanding of the complex pathological mechanisms involved in the generation of chronic inflammatory pain in SCI. These findings enable us to identify and validate several potent natural analgesic-anti-inflammatory drug candidates with minimal side effects. However, these compounds have been studied in preclinical models and shown promising results, but no clinical studies have been performed. Therefore, a detailed exploration of these natural compounds is important for bringing them from bench to bedside.