The microbiome is a community of various microorganisms that inhabit or live on the skin of humans/animals, sharing the body space with their hosts. It is a sort of complex ecosystem of trillions of commensals, symbiotic, and pathogenic microorganisms, including trillions of bacteria, archaea, protozoa, fungi, and viruses. The microbiota plays a role in the health and disease status of the host. Their number, species dominance, and viability are dynamic. Their long-term disturbance is usually accompanied by serious diseases such as metabolic disorders, cardiovascular diseases, or even cancer. While epigenetics is a term that refers to different stimuli that induce modifications in gene expression patterns without structural changes in the inherited DNA sequence, these changes can be reversible or even persist for several generations. Epigenetics can be described as cell memory that stores experience against internal and external factors. Results from multiple institutions have contributed to the role and close interaction of both microbiota and epigenetics in disease induction. Understanding the mechanisms of both players enables a better understanding of disease induction and development and also opens the horizon to revolutionary therapeutic approaches. The present review illustrates the roles of diet, microbiome, and epigenetics in the induction of several chronic diseases. In addition, it discusses the application of epigenetic data to develop diagnostic biomarkers and therapeutics and evaluate their safety for patients. Understanding the interaction among all these elements enables the development of innovative preventive/ therapeutic approaches for disease control.