Global consumption of smokeless tobacco (SLT) reached 300 million users worldwide majorly from middle-income countries. More than 4000 chemical compounds represent it as one of the noxious consumable products by humans. Besides toxicants/carcinogens, the heavy microbial load on smokeless tobacco further keeps human health at higher risk. Several of these inhabitant microbes participate in biofilm formation and secrete endotoxin/mycotoxins and proinflammatory-like molecules, leading to several oral diseases. Tobacco-associated bacteria exhibit their role in tobacco-specific nitrosamines (TSNAs) formation and acetaldehyde production; both are well-documented carcinogens. Moreover, tobacco exhibits the potential to alter the oral microbiome and induce dysbiotic conditions that lead to the onset of several oral and systemic diseases. Traditional cultivation approaches of microbiology provide partial information of microbial communities of a habitat; therefore, microbiomics has now been employed to study the metagenomes of entire microbial communities. In the past 5 years, few NGS-based investigations have revealed that SLT harbors four dominant phyla (Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes) dominating Bacillus spp. and/or Pseudomonas spp. However, functional characterization of their genetic elements will be a more informative attribute to understand the correlation between inhabitant microbial diversity and their relatedness concerning abundance and diseases. This review provides an update on the microbial diversity of SLT and its associated attributes in human health.