The study of the microbiome has changed our overall perspective on health and disease. Although studies of the lung microbiome have lagged behind those on the gastrointestinal microbiome, there is now evidence that the lung microbiome is a rich, dynamic ecosystem. Tuberculosis is one of the oldest human diseases, it is primarily a respiratory infectious disease caused by strains from the Mycobacterium tuberculosis Complex. Even today, during the COVID-19 pandemic, it remains one of the principal causes of morbidity and mortality worldwide. Tuberculosis disease manifests itself as a dynamic spectrum that ranges from asymptomatic latent infection to life-threatening active disease. The review aims to provide an overview of the microbiome in the tuberculosis setting, both in patients’ and animal models. We discuss the relevance of the microbiome and its dysbiosis, and how, probably through its interaction with the immune system, it is a significant factor in tuberculosis’s susceptibility, establishment, and severity.