Purpose Tumor necrosis factor (TNF)-stimulated gene-6 (TSG-6), a secreted protein associated with inflammation, is believed to possess momentous and multiple anti-inflammatory and tissue-protective properties. However, the role and potential mechanism of TSG-6 in cervical disk degeneration (CDD) are still not clear. Hence, we aimed to explore the effect of TSG-6 on CDD. Methods Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) or enzyme-linked immunosorbent assay was applied to detect the expression level of TSG-6 and IL-1β in normal and degenerated nucleus pulposus (NP) tissues. Then, qRT-PCR and western blot were adopted to test the TSG-6 protein expression after IL-1β treatment (10 ng/mL) in human NP cells (HNPCs). After over-expressing TSG-6, qRT-PCR was also utilized to evaluate the expression of TNF-α, IL-8, and IL-6 and the synthesis of sulfated glycosaminoglycans (sGAGs), western blot to check the expression of extracellular matrix (ECM) proteins [collagen II, aggrecan, and matrix metalloproteinase-3 (MMP-3)], pain-related molecules (CGRP, calcitonin gene-related peptide; NGF, nerve growth factor; SP, substance P), and PI3K/Akt signaling pathway-related proteins. Results Briefly speaking, TSG-6 and IL-1β expression levels were significantly increased in CDD patient tissues; and IL-1β treatment could significantly increase TSG-6 expression in HNPCs. Further research revealed that, in addition to greatly promoting sGAGs synthesis, TSG-6 over-expression also inhibited TNF-α, IL-8, and IL-6 expression and ECM degradation in IL-1β-induced HNPCs. (The collagen II and aggrecan expression was up-regulated and MMP-3 expression was down-regulated.) Furthermore, over-expression of TSG-6 could decrease the levels of CGRP, NGF, and SP protein expression and activate the PI3K/Akt signaling pathway in IL-1β-treated HNPCs. Conclusion TSG-6 inhibits inflammatory responses, ECM degradation, and expression of pain-related molecules in IL-1β-induced HNPCs by activating the PI3K/Akt signaling pathway.