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Spinal cord injuries (SCI) are associated with significant physical and economic burdens on individuals and healthcare systems. Research has shown that several molecular and cellular interactions significantly contribute to SCI progression. The initiation and development of SCI are strongly linked to cellular stress mechanisms, notably those associated with the endoplasmic reticulum (ER), which gives rise to the unfolded protein response (UPR). This systematic review discusses the molecular pathways involved in ER stress, particularly the role of the activating transcription factor 6 (ATF6)-mediated apoptosis pathway and the role of CCAAT/enhancer-binding homologous protein (CHOP) in SCI pathogenesis. Prolonged ER stress exacerbates neuronal degeneration and apoptosis, making it a key factor in SCI. Efforts to inhibit this pathway via genetic or pharmacological interventions have shown potential in addressing cellular dysfunction and preventing SCI-related degeneration. Moreover, pharmacological approaches that mitigate ER stress, for example, by promoting protein folding, are promising for enhancing neuronal survival and reducing damage after SCI. Complementary strategies, such as maintaining metabolic health and engaging in physical activity, could also help fortify the spinal cord against ER stress-related damage. These preventive and therapeutic approaches underscore the importance of targeting ER stress to minimize SCI onset and progression, offering valuable insights for improved care and recovery.