We report a case of Histoplasma-associated hemophagocytic syndrome in a diabetes mellitus patient. The patient presented with a fever, cough, and an ulcer on the tongue. The biopsy confirmed the diagnosis of histoplasmosis from the tongue ulcer. Other investigations revealed normal clusters of differentiation 4 (CD4) count and increased hemoglobin A1c (HbA1c) and lactate dehydrogenase (LDH) levels. The patient was diagnosed with hemophagocytic syndrome secondary to Histoplasma after fulfilling the hemophagocytic lymphohistiocytosis (HLH)-2004 criteria required for diagnosis, including fever (with peak temperatures of >38.5° C), splenomegaly, cytopenia affecting two cell lineages in peripheral blood, hypertriglyceridemia (fasting triglycerides >265 mg/dL), and hemophagocytosis in the bone marrow biopsy. The patient was started on injection amphotericin B with remarkable improvement.