: Spinal cord injury (SCI) is a complex medical condition with widespread effects that extend beyond motor and sensory impairments. In addition to nervous system damage, SCI patients experience various secondary complications, including vascular dysfunction, altered body composition, and metabolic disturbances. Among the most common secondary pathologies is the development of pressure injuries (PIs), chronic wounds that significantly affect quality of life and can be challenging to treat. Understanding the physiological and cellular mechanisms behind these complications is crucial for improving care and therapeutic outcomes. : We conducted a comprehensive literature search in PubMed, Scopus, and Google Scholar using keywords related to spinal cord injury, pressure ulcer/pressure injuries, metabolic and vascular dysfunction, biomechanics, and regenerative therapies. Studies were selected based on their relevance to the pathophysiology, risk factors, and novel therapeutic approaches for PIs in SCI patients. : Vascular dysfunction, characterized by impaired blood flow and microcirculatory issues, predisposes SCI patients to ischemia and tissue necrosis, particularly in areas subjected to prolonged pressure. Additionally, changes in body composition, such as increased adiposity and muscle atrophy, further compromise tissue integrity and healing capacity. The inflammatory response, mediated by cytokines such as IL-1, IL-6, and TNF-α, exacerbates these effects by sustaining a pro-inflammatory environment that delays the transition of macrophages to the M2 phenotype, critical for wound healing. External factors, such as poor nutrition, infections, and immobility, also play a significant role in worsening the wound healing process. : Chronic SCI induces a cascade of physiological changes that predispose patients to the development of PIs and complicate their recovery. The intricate interplay of vascular, metabolic, and inflammatory responses creates a hostile environment for wound healing. A deeper understanding of these systemic effects is essential not only for developing targeted therapeutic strategies to improve chronic wound healing but also for refining preventive approaches that minimize their occurrence. Advancing this knowledge will ultimately help enhance the quality of life for individuals with SCI.