The majority of cases with tuberculous pleuritis have negative acid-fast bacilli (AFB) on smear microscopy, making the diagnosis difficult. This case report is based on the successful diagnosis and management of an extra-pulmonary (EP) multidrug-resistant tuberculosis (MDR-TB) patient with a history of lymphoma. Initial tests revealed a right-sided pleural effusion and thickening of the pleura. The closed pleural biopsy, pleural fluid histopathology, culture, and drug sensitivity testing (DST) report revealed Mycobacterium tuberculosis with isoniazid and rifampicin resistance. Based on the DST report, the patient was labeled as a case of MDR-TB and successfully managed with an individualized drug-resistant TB (DR-TB) regimen. With initial negative microscopy and GeneXpert MTB/RIF (Sunnyvale, CA: Cepheid Inc.) reports, this case demonstrated that DR-TB could exist even in the absence of risk factors. Furthermore, it also unveils the importance of line probe assays (LPAs) and culture in identifying MDR-TB. Lymphocytic/exudative pleural effusions and pleural biopsy specimens should be subjected early on to investigations like Xpert/MTB RIF, cultures, and genotypic DST to timely diagnose and treat DR-TB.