Infectious diseases have long posed a significant threat to global health and require constant innovation in treatment approaches. However, recent groundbreaking research has shed light on a previously overlooked player in the pathogenesis of disease—the human microbiome. This review article addresses the intricate relationship between the microbiome and infectious diseases and unravels its role as a crucial mediator of host–pathogen interactions. We explore the remarkable potential of harnessing this dynamic ecosystem to develop innovative treatment strategies that could revolutionize the management of infectious diseases. By exploring the latest advances and emerging trends, this review aims to provide a new perspective on combating infectious diseases by targeting the microbiome.