Abstract: Periodontitis is a prevalent chronic infectious and inflammatory disease worldwide, which imposes harms extending far beyond the oral cavity. A large body of research has demonstrated that periodontitis is closely associated with various systemic diseases, such as diabetes mellitus, cardiovascular diseases, inflammatory bowel disease, and rheumatoid arthritis. Serving as a crucial pathway connecting the oral cavity to the entire body, the oral-gut axis becomes the core mechanism through which periodontitis affects systemic health, primarily via the ectopic colonization of salivary microbiota, intestinal dysbiosis, intestinal barrier disruption, and systemic inflammation. This review summarizes recent studies focusing on how periodontitis influences systemic comorbidities via the oral-gut axis, encompassing clinical studies, animal experimental and in vitro research. We summarize the research progress regarding how periodontitis perturbs intestinal homeostasis through ectopic colonization of oral pathogenic bacteria, immunoinflammation, host factor regulation, and metabolic disorders, and eventually affects systemic diseases via the oral-gut axis. This review aims to provide a new perspective for the prevention and treatment of periodontitis-related systemic comorbidities.