Cluster of differentiation 38 (CD38) is a multifunctional cell surface protein involved in nicotinamide adenine dinucleotide (NAD) homeostasis in types of cells and tissues, which can be found in many immune cells and non-immune cells. Previous studies have shown that CD38 plays an important role in regulating innate immunity. Recently, many studies have revealed the importance of CD38 in autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type 1 diabetes (T1D) and inflammatory bowel disease, among others. In this report, we will briefly discuss the complex immunological functions of CD38 and focus on recent advances in the role of CD38 in the development and pathogenesis of autoimmune diseases, as well as their potential as therapeutic targets for systemic diseases, intending to make a comprehensive understanding of CD38 and its promising therapeutic potential in these systemic diseases.