Circulating cell-free DNA (cfDNA) is a large molecule that plays a central role in the pathogenesis of SLE. It is the target antigen of autoantibodies and the main component of immune complexes. Due to the large differences in the content of cfDNA detected in different studies, cfDNA cannot be used as a strong diagnostic basis for SLE at present. As an active component of cfDNA, the correlation between double-stranded DNA (dsDNA) and SLE has not been fully studied. The detection of dsDNA may provide a more accurate diagnosis and treatment basis for SLE, and the in-depth study of SLE patients is helpful to further understand the pathogenesis of SLE. Blood samples were collected from 173 SLE patients and 2970 healthy controls. The concentration of serum dsDNA was determined by fluorescence quantitative method. Propensity score matching (PSM) method was used to match 444 healthy controls and 148 SLE patients according to age and gender. Serum dsDNA levels were compared between SLE patients and matched healthy controls. At the same time, blood exosomes were extracted to explore the correlation between serum dsDNA and exosome dsDNA. As demonstrated herein, serum dsDNA levels in SLE patients were shown to be considerably higher than in healthy controls. Meanwhile, In SLE patients, serum dsDNA level was correlated with season and other clinical indicators, but not with temperature and ultraviolet. Additionally, a statistically significant connection between serum and exosome dsDNA was discovered. We also found that the gene encoding the dsDNA receptor was upregulated. The presented data suggest that detection of dsDNA is promising as a rapid and simple tool for assessing disease progression in SLE, which can help physicians and patients in disease management. The mechanism of elevated dsDNA in SLE patients requires more research.