Intervertebral disc (IVD) degeneration is a major cause of low back pain (LBP), a significant global health burden. While glycosylation plays a key role in cellular signaling and inflammation, its role in IVD degeneration remains poorly understood. This study characterizes glycan alterations in human healthy and degenerated IVDs using glycomic (UPLC‐MS, MALDI‐IMS) and proteomic (LC‐MS) analyses, combined with functional studies. These results identify hypersialylation, especially α‐2,6‐linked sialic acid, as a prominent feature of degenerated IVDs. In vitro inhibition of sialylation (3Fax‐peracetyl Neu5Ac) in nucleus pulposus cells demonstrates reduced oxidative stress and inflammatory signaling, indicating a functional role for hypersialylation in IVD pathology. Targeting glycosylation pathways, notably sialylation, emerges as a promising therapeutic strategy for IVD degeneration.