Periodontitis is increasingly recognized for its role in overall health and its associations with systemic conditions. Shared etiological factors, including microbiological, immunological, genetic, and environmental influences, have prompted interest in the potential impact of periodontal therapy on broader health outcomes. The oral microbiome plays a key role in the pathogenesis of periodontitis, with microbial imbalances (dysbiosis) contributing to inflammation and systemic disease progression. Additionally, immune responses to periodontal infection, such as chronic inflammation and dysregulated immune activity, are central to linking periodontitis with conditions like diabetes, cardiovascular disease, and autoimmune disorders. This chapter explores the connections between periodontal treatment and systemic diseases, such as diabetes, rheumatoid arthritis, cardiovascular disease, chronic kidney disease, Alzheimer’s disease, digestive disorders, and respiratory disease. It also reviews the current research on the mechanisms, including microbial and immune factors, that underlie these associations. By emphasizing the role of periodontal health, the oral microbiome, and immune regulation in disease prevention and management, this chapter underscores the importance of integrated healthcare approaches to improve patient outcomes.