The present study was designed to identify and understand the potential effectiveness of therapeutic target in intervertebral disc degeneration (IVDD) and its regulation mechanism. The role and mechanism of interleukin-18 (IL-18) in the disease were investigated. The IVDD degenerative nucleus pulposus (NP) tissues from the human and mouse models were used.A total of three groups of Male BALB/c mice were randomly made i.e control, IVDD, and IVDD+Ad-shIL-18 groups. After Ad-shIL-18 transfection, the expression of ECM synthesis related protein Aggrecan (ACAN) and Collagen II, apoptotic effector Caspases (Caspase-3, 8, 9, 12 and Cleaved-Caspase 3, 8, 9, 12), pro-apoptotic gene Bax and anti-apoptotic factors Bcl-2 in NP cells of the human were evaluated. The results of our study revealed that the mRNA and protein expression levels of IL-18 were notably increased in the NP tissues of IVDD patients and mice models. In the IVDD mice model, Ad-sh-IL-18 treatment reversed the IVDD progression. The levels of Aggrecan and Collagen II, contributing to ECM degradation in NP cells, were also significantly increased. Additionally, Ad-sh-IL-18 could inhibit the NP cell's apoptosis via regulating the caspase-3/9 pathway. The IL-18 knockdown via the caspase-3/9 pathway, might reduce the NP cell's death as well as the imbalance between catabolism and anabolism of ECM in IVDD.