Over the past two decades, the importance of microbiota in health and disease has become evident. The human gut microbiota and oral microbiota are the largest and second-largest microbiome in the human body, respectively, and they are physically connected as the oral cavity is the beginning of the digestive system. Emerging and exciting evidence has shown complex and important connections between gut microbiota and oral microbiota. The interplay of the two microbiomes may contribute to the pathological processes of many diseases, including diabetes, rheumatoid arthritis, nonalcoholic fatty liver disease, inflammatory bowel disease, pancreatic cancer, colorectal cancer, and so on. In this review, we discuss possible routes and factors of oral microbiota to affect gut microbiota, and the contribution of this interplay between oral and gut microbiota to systemic diseases. Although most studies are association studies, recently, there have been increasing mechanistic investigations. This review aims to enhance the interest in the connection between oral and gut microbiota, and shows the tangible impact of this connection on human health.