A subset of bacterial species that holds genes encoding for β-glucuronidase and β-galactosidase, enzymes involved in the metabolism of conjugated estrogens, is called the "estrobolome." There is an emerging interest embracing this concept, as it may exert a selective impact on a number of pathologies, including oral cancer. Although the estrobolome bacteria are typically part of the gut microbiota, recent experimental pieces of evidence have suggested a crosstalk among oral and gut microbiota. In fact, several oral bacterial species are well represented also in the gut microbiota, and these microbes can effectively induce the estrobolome activation. The main pathways used for activating the estrobolome are based on the induction of the expression patterns for 2 bacterial enzymes: β-glucuronidase and aromatase, both involved in the increase of estrogen released in the bloodstream and consequently in the salivary compartment. Mechanistically, high estrogen availability in saliva is responsible for an increase in oral cancer risk for different reasons: briefly, 1) estrogens directly exert biological and metabolic effects on oral mucosa cells; 2) they can modulate the pathological profile of some bacteria, somewhere associated with neoplastic processes (i.e., spp., ssp.); and 3) some oral bacteria are able to convert estrogens into carcinogenic metabolites, such as 4-hydroxyestrone and 16α-hydroxyestrone (16α-OHE), and can also promote local and systemic inflammation. Nowadays, only a small number of scientific studies have taken into consideration the potential correlations among oral dysbiosis, alterations of the gut estrobolome, and some hormone-dependent cancers: this lack of attention on such a promising topic could be a bias affecting the full understanding of the pathogenesis of several estrogen-related oral pathologies. In our article, we have speculated on the activity of an oral-gut-estrobolome axis, capable of synergizing these 2 important microbiotas, shedding light on a pilot hypothesis requiring further research.