Aim and background: Non-Hodgkin lymphoma (NHL) is the most common hematological malignancy, and diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype. It is a highly aggressive B-cell lymphoma resulting in the clonal proliferation of a germinal or post-germinal malignant B cell. The diagnosis is confirmed by biopsy of the affected node/extra-nodal site. Pleural involvement in lymphoma has a diverse presentation; however, presentation as an empyema, as in our case, has not been reported previously. Case description: We present a very rare case of a young, previously healthy female patient who presented with a right-sided pleural collection, who was initially suspected to have empyema due to characteristic findings on ultrasonography and pleural fluid appearance. Her pleural fluid cytology revealed atypical cells and was later diagnosed with an underlying anterior mediastinal mass confirmed to be DLBCL. Conclusion: Empyema may be the first harbinger of malignancy, especially in young immunocompetent patients. Timely diagnosis may be challenging but it improves the prognosis of such patients. Clinical significance: In a TB-endemic country like India, a patient with empyema poses a diagnostic dilemma. Cytology/biopsy and immunohistochemistry aid in diagnosis in such cases. Imaging also plays a key role in tumor staging, therapeutic planning, and follow-up of patients.