Neonatal systemic lupus erythematosus (NLE) is an acquired autoimmune disease. The presence of effusions, such as pleural effusion and pericardial effusion, is rare. The present study helped investigate the clinical characteristics and progression of children with NLE combined with effusions. Clinical data of patients diagnosed with NLE were retrospectively collected and analyzed from January 1, 2011, to December 31, 2023, at the Children's Hospital of Soochow University and Suzhou Municipal Hospital. Patients with NLE were divided into effusion and non-effusion groups based on the presence of effusion. Moreover, the clinical data of the newborns in both groups were compared and investigated. Eleven (11/45, 24.44%) NLE patients had effusions, such as pleural effusion, testicular hydrocele, peritoneal effusion, pericardial effusion, and hydrocephalus. Other organs involved in effusion patients were cutaneous, gastrointestinal, hematologic, cardiac, and neurological. Among the patients with effusion, five cases of SLE in pregnant mothers, two cases of Sjogren's syndrome, one case of photoallergic symptoms, and three of pregnant mothers with no history of antenatal autoimmune disease. Pregnant mother' autoimmune disease in remission prior to pregnancy, or stable low disease activity. Seven patients were positive for Anti-SSA, five of which were double positive for Anti-SSA and Anti-SSB. Compared with the non-effusion group, the effusion group patients had significantly higher lactate dehydrogenase, creatine kinase, and fibrinogen, significantly lower platelets, total protein, and albumin. These patients were likelier to have thrombocytopenia and coagulation abnormalities. Logistics regression analysis demonstrated that NLE patients with effusions are more likely to have decreased serum total protein levels. All NLE patients with effusion have self-resorption of the effusion. 24.44% of patients had effusions in our study. NLE patients with effusion are more likely to have hematologic involvement and a more inflammatory response. The effusion in NLE patients is usually self-resorption, severe cases can be treated with nonsteroidal anti-inflammatory drugs/steroids. Key Points • NLE patients combined with effusions and were self-limiting, with pleural effusion being the most common. • NLE patients combined with effusions have a more inflammatory response, significant abnormalities in the blood routine and biochemical-related indexes.