Intervertebral disc degeneration (IDD) is a major cause of low back pain and disability, and although magnetic resonance imaging remains a standard diagnostic tool, it provides only limited insight into the cellular and molecular changes in the discs. The systematic review included studies published between 2015 and 2025 from PubMed, Scopus and Web of Science databases that analyzed histological and immunohistochemical changes in degenerated human discs. Common histopathological features of degeneration included extracellular matrix disorganization, loss of proteoglycans, fibrosis, new vessel formation, and cell clumping. At the molecular level, an increased activity of catabolic enzymes, inflammatory cytokines, apoptotic mediators and factors supporting the formation of new blood vessels was found, while regenerative and protective markers were significantly reduced. Analysis of protein interactions revealed regionally specific degenerative pathways: extracellular matrix remodeling and BMP/VEGF signaling in the disc nucleus, inflammation and mechanotransduction in the nucleus pulposus, and ossification and prostaglandin signaling in endplate cartilage. Histological analysis appears to be a necessary adjunct to imaging methods to accurately characterize intervertebral disc degeneration and identify potential biomarkers and therapeutic targets.