Tuberculosis (TB) is among the most predominant infectious illnesses in developing areas around the globe. As stated by the World Health Organization (WHO), the number of instances of drug-resistant tuberculosis (DR-TB) has increased lately. This case report describes the effective diagnosis and customized treatment for primary extra-pulmonary multidrug-resistant tubercular pleural effusion, a disease which is difficult to identify due to relatively low bacterial count as well as frequently negative staining on Ziehl Neelsen (ZN) for acid-fast bacilli (AFB). The bacteria causing multidrug-resistant tuberculosis (MDR-TB) is resistant to a minimum of two drugs, isoniazid and rifampicin, the most effective TB medications. We are going to present the case of a 60-year-old male who complained of breathlessness, cough, and loss of weight for one month and chest pain and fever for 12 days. The patient's pleural fluid examination was carried out, which showed exudative fluid (according to Light's criteria) with adenosine deaminase (ADA) positive. Cartridge-based nucleic acid amplification test (CBNAAT) and line probe assays (LPAs) were carried out, which suggested
mycobacterium tuberculosis
(MTB)
with rifampicin and isoniazid resistance. The patient was started an oral regimen with bedaquiline in accordance with WHO standards, leading to significant improvement. This case reveals that to promptly diagnose and treat DR-TB, pleural effusions, and pleural biopsies need to be exposed early to investigations such as Xpert (MTB)/resistance to rifampicin assay, culturing, and genotype drug sensitivity testing (DST).