Background: Diffuse large B-cell lymphoma (DLBCL) is a common subtype of non-Hodgkin lymphoma of B-lymphocyte origin, characterized by an aggressive clinical course. Clinically, it most often presents with lymphadenopathy and “B symptoms,” including fever, night sweats, and weight loss. However, in some cases, the disease predominantly involves extranodal organs, such as the spleen, and may present with nonspecific manifestations, thereby posing a diagnostic challenge. Case presentation: A 36-year-old male patient presented with high-grade fever of unknown origin, dyspnea, generalized weakness, sweating, and a 7–8 kg weight loss over one month. Clinical evaluation and laboratory investigations revealed massive splenomegaly measuring 15 × 20 × 20 cm, progressive thrombocytopenia, anemia, and elevated C-reactive protein and lactate dehydrogenase levels. Diagnostic workup for infection, tuberculosis, viral infection, and autoimmune disease did not reveal findings sufficient to establish an alternative diagnosis. Because focal splenic lesions and suspected splenic infarction were identified, splenectomy was performed. Histopathological and immunohistochemical examination of the splenic tissue demonstrated CD20+, CD79a+, BCL2+, CD3−, CD8−, CD30−, and ALK− expression, confirming the final diagnosis of diffuse large B-cell lymphoma. Although DLBCL itself is a common form of non-Hodgkin lymphoma, this case is clinically rare and diagnostically challenging because it presented with predominant splenic involvement, massive splenomegaly measuring 15×20×20 cm, treatment-resistant fever, progressive thrombocytopenia, and imaging findings mimicking splenic infarction. Conclusion In patients presenting with fever of unknown origin that is resistant to treatment, massive splenomegaly, thrombocytopenia, elevated LDH, and increased inflammatory markers, lymphoproliferative disorders should be considered early in the differential diagnosis in addition to infectious causes. Histopathological and immunohistochemical examination play a crucial role in confirming the diagnosis.