Non-tuberculous mycobacterial species are uncommon human pathogens. They are divided into slow and rapid growing mycobacteria (RGM) with Mycobacterium smegmatis group as an uncommon pathogen among the RGM. A 19 years old male presented with a 1 month history of dyspnea, orthopnea, unintentional weight loss, palpitation, flu-like symptoms and dry cough. Physical examination revealed tachycardia, distended superficial chest veins with a decrease in breath sounds at the right lower lung with fine crepitations. CT of the chest showed a large anterior mediastinal mass infiltrating the pericardium and three chambers of the myocardium that was confirmed using echocardiography. Despite negative workup for tuberculosis, the patient was treated successfully using first-line anti-TB treatment, which was begun before the tissue culture grew M. smegmatis. To our knowledge, this is the first case in the literature of M. smegmatis infection mimicking cardiomediastinal tuberculoma, and RGM should be suspected in similar presentations with negative TB workup, even in an immunocompetent patient. This is also the first patient to be treated using only first-line anti-tuberculous treatment successfully in the literature.