Hyaluronic acid is widely recognized as a therapeutic target and is currently utilized in medical applications. However, the metabolism of HA during intervertebral disc degeneration has not been fully elucidated. The effects of hyaluronidase on the cartilage endplate remain unclear. The aim of this article is to explore the effects of hyaluronidase on cartilage endplate (CEP) cells and potential molecular mechanisms. Cartilage endplate cells were extracted from the intervertebral endplates of 4-week-old rats. These cells were then treated with hyaluronidase. Cell viability was detected using Cell Counting Kit-8. Cell apoptosis and extracellular matrix degradation were determined using RT-PCR. Additionally, Transcriptome sequencing was performed and prostaglandin-endoperoxide synthase-2 (PTGS2) was identified as the key factor in hyaluronidase-induced degeneration. Furthermore, we inhibited PTGS2 and measured the level of apoptosis mediators to determine its effect on hyaluronidase-induced CEP degeneration. Exposure to hyaluronidase significantly reduced cell viability, induced apoptosis of CEP cells and promoted extracellular matrix degradation in vitro. Hyaluronidase treatment upregulated PTGS2 in CEP cells. Knockdown of PTGS2 alleviated the apoptosis of CEP cells and inihited extracellular matrix degradation caused by hyaluronidase. Hyaluronidase induces endplate cell apoptosis and extracellular matrix degradation in vitro, while PTGS2 functions as a regulatory factor in this process. Inhibiting PTGS2 may serve as an effective treatment for intervertebral disc degeneration.