Recent findings from multimodal imaging studies point to macrostructural pathological changes in areas significantly distant from the epicenter of spinal cord injury, both in the spinal cord and in the brain. Studies are being performed to determine cellular and molecular mechanisms of these shifts, which are currently poorly understood. Research has demonstrated that the pathological process in the remote area is multifaceted. This process involves astrocytes and microglia, which contribute to the degeneration of nerve fibers passing from and through the immediate impact area, as well as participate in reciprocal activation. As a result, there is accompanying synaptic loss in areas remote to the spinal cord injury location. Reactive astrocytes produce chondroitin sulfate proteoglycans that inhibit axon growth and damage cells. However, neuronal death in the remote area remains controversial. The area of primary injury is the source of numerous neurotoxic molecules that release into the cerebrospinal fluid. It is assumed that these molecules, primarily matrix metalloproteinases, disrupt the blood-spinal cord barrier, which leads to tissue infiltration by macrophage precursors in the remote area. Activated macrophages secrete pro-inflammatory cytokines and matrix metalloproteinases, which, in turn, induce astrocytes and microglia towards a pro-inflammatory phenotype. In addition, reactive microglia, together with astrocytes, secrete numerous pro-inflammatory and neurotoxic molecules that activate inflammatory signaling pathways, consequently exacerbating synaptic depletion and neurological deterioration. It appears likely that the interplay between chronic inflammation and neurodegeneration is a pivotal characteristic of the pathological process in the spinal cord areas distant from the epicenter of the lesion. Pathological changes in the distant areas should be the object of research as potential therapeutic targets.