Periodontitis is a chronic, multifactorial inflammatory disease characterized by progressive destruction of the tooth-supporting structures, including the gingiva, periodontal ligament, cementum, and alveolar bone. It represents a major public health concern due to its high prevalence and its role as a leading cause of tooth loss in adults. The disease is initiated by a dysbiotic microbial biofilm but is primarily driven by an exaggerated and dysregulated host immune-inflammatory response. In recent years, considerable research interest has been directed towards the identification of biological markers that can reflect disease activity, progression, and response to therapy. Among the various biological fluids, saliva and serum have emerged as promising diagnostic media due to their ability to reflect local and systemic inflammatory processes, respectively. This review of literature elaborates on the pathophysiology of periodontitis, the role of inflammatory mediators, and the current evidence supporting the use of salivary and serum biomarkers in predicting disease progression and monitoring therapeutic outcomes.