Background: The coronavirus disease 2019 (COVID-19) infection is considered the most detrimental among patients with comorbid conditions during the prevaccination era. Drugs have been repurposed for the management of COVID-19 infection. An attempt was made to study the morbidity and mortality outcome and the role of anti-TB drug therapy in COVID-19 disease prognosis, in patients of tuberculosis (TB) on anti-TB drug therapy acquiring COVID-19 infection. Materials and methods: For this study patients diagnosed with COVID-19 infection with TB were divided into three groups. Group I—patients with TB and COVID-19 infection, Group II—patients on anti-TB therapy who acquired COVID-19 infection and Group III—patients suspected with coronavirus disease 2019 (COVID-19) infection, found to be COVID-19 negative and diagnosed with TB from March 2019 to June 2021. All were studied for the duration of hospital stay, clinical symptoms, and associated comorbidity. Kruskal–Wallis and Chi-squared tests were applied. Result: From records of the designated microscopic center (DMC) of Government Medical College, Surat, a total of 888 patients were diagnosed with TB during the study period, 46 of whom reported to the COVID-19 care center with clinical suspicion. Out of 46 patients, 52.2% had TB, 23.9% had diabetes, 15.2% had hypertension, 4.3% had chronic kidney disease (CKD) with DM & HT, 2.1% had rheumatoid arthritis (RA). Out of a total of 46 patients, 41 recovered, while five died. The median duration of disease among patients from all groups was 15 days. There was a significant association between TB patients on AKT with COVID-19 test results. Those patients who were on AKT had lesser chances of getting an infection with COVID-19 (χ² = 272.41, p < 0.00001). Conclusion: The study observation leads toward anti-TB drugs having a protective role against COVID-19 infection.