Langerhans cell histiocytosis (LCH) is a rare disease characterized by the clonal accumulation and/or proliferation of specific dendritic cells resembling normal epidermal Langerhans cells (LCs). Clinical manifestations are variable, depending on the affected tissues or organs, however, LCH with elevated serum IgG4 has not been reported. Herein, we reported a 26-year-old Chinese female multi-system LCH (MS-LCH) who first presented with central diabetes insipidus (CDI), accompanied by panhypopituitarism and hepatic dysfunction. Diagnostic investigations were strongly suspicious of IgG4-RD because of elevated serum IgG4 levels during the process. Furtherly, thyroid and lymph node involvement and biopsy led to the diagnosis of MS-LCH; the strongly positive staining of CD1a, S100, CD207 (langerin), and Ki67 was found. Moreover, after systemic treatment with five cycles of chemotherapy, many lesions were greatly improved. Since both LCH and IgG4-RD are orphan diseases that can affect any organ, the differential diagnosis is challenging, especially when LCH is associated with unexplained serum IgG4 elevation. In this article, the case of a young woman suffering from MS-LCH that affected organs including the pituitary, thyroid, lymph node, and liver was summarized, and relevant literature was reviewed to better equip the diagnosis and treatment in its early stages.