<p>UFMylation, similar to ubiquitination, is a unique post-translational modification which is indispensable in hematopoiesis, neurogenesis and chondrogenesis. However, its role in intervertebral disc development remains unclear. In this study, we focused on DDRGK domain containing protein 1 (DDRGK1), a pivotal component involved in UFMylation, and generated <i>Ddrgk1</i>^fl/fl; <i>Acan-CreER</i>^<i>T2</i> (<i>Ddrgk1</i>^cKO) mice to explore DDRGK1’s regulatory function in the nucleus pulposus and cartilage endplate. We found that <i>Ddrgk1</i> conditional knockout led to severe retardation of spinal growth, disruption of disc cellularity and initiation of disc degeneration during early postnatal phase. Furthermore, <i>Ddrgk1</i> conditional knockout in late postnatal phase resulted in profound degeneration of mouse discs, mainly characterized by substantially reduced thickness of cartilage endplate. In addition, <i>Ddrgk1</i>^cKO mice exhibited exacerbated disc degeneration compared to the WT mice after the lumbar spine instability surgery. RNA sequencing of disc cells from <i>Ddrgk1</i>^cKO mice showed upregulation of genes related to apoptosis, matrix metalloproteinase activation, extracellular matrix (ECM) degradation and endoplasmic reticulum (ER) unfolded protein response after <i>Ddrgk1</i> conditional knockout. Immunohistochemical analysis further verified increased apoptosis, ECM disruption and ER stress in both nucleus pulposus and cartilage endplate after <i>Ddrgk1</i> conditional knockout. In summary, this study demonstrated that DDRGK1 preserves the normal cellularity and structure of intervertebral discs by regulating the cell fate of nucleus pulposus and cartilage endplate cells, maintaining the ER homeostasis and regulating the metabolic balance of ECM.</p>