Fever of unknown origin (FUO) remains a diagnostic challenge, particularly when associated with hepatosplenomegaly and cytopenias. We report the case of a 44-year-old woman presenting with low-grade fever and lower abdominal pain for two months, followed by vomiting and bleeding manifestations. Examination revealed pallor and significant hepatosplenomegaly. Laboratory evaluation demonstrated elevated inflammatory markers and progressive thrombocytopenia. Urine culture grew Escherichia coli sensitive to piperacillin–tazobactam; however, fever persisted despite appropriate antibiotic therapy. Extensive infectious and autoimmune workup was negative. The constellation of persistent fever, hepatosplenomegaly, cytopenias, and poor response to antibiotics raised suspicion of an underlying hematological or inflammatory disorder. This case highlights the complexity of evaluating prolonged fever and underscores the importance of considering non-infectious etiologies when clinical response is inadequate.