The activating receptor natural killer group 2 member D (NKG2D) and its ligands, the UL16-binding protein (ULBP), play pivotal roles in autoimmune diseases, characterized by multidimensional regulatory features. This review employs a three-dimensional framework of "ligand supply-ligand fate-receptor regulation" to analyze the research progress of the ULBP-NKG2D axis in autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and Crohn disease. In systemic lupus erythematosus, the axis involves both peripheral immune suppression (driven by receptor internalization) and local tissue immune attack, collectively shaping the complex pathology. In rheumatoid arthritis, the core pathological dysre-gulation of the axis is concentrated in the inflammatory synovial microenvironment: membrane-bound ligands derived from synovial fibroblasts directly drive the cytotoxicity of local effector cells, exacerbating joint inflammatory damage, while these ligands may be cleaved by a disintegrin and metalloprotease 10 (ADAM10) into soluble forms that enter the circulation and mediate peripheral immunosuppression. In type 1 diabetes, pancreatic β cells directly trigger NKG2D-mediated immune killing by upregulating membrane-bound ULBP proteins. In multiple sclerosis, astrocyte-derived ULBP4, in both membrane-bound and soluble forms, enhances the migration and pro-inflammatory capacity of effector cells. In Crohn disease, endoplasmic reticulum stress induces widespread ULBP expression in intestinal epithelial and endothelial cells, collectively mediating immune cell recruitment and amplifying local inflammation. This review also summarizes the current status of innovative drugs targeting the NKG2D receptor and their clinical translation progress, aiming to provide a reference for unraveling the complex immunopathology and developing precision immunotherapy strategies.