Periodontitis (Pd) is a prevalent chronic inflammatory disease of the periodontium, leading to progressive destruction of tooth-supporting tissues. Early diagnosis is crucial to prevent disease progression and improve therapeutic outcomes. Saliva has emerged as a promising diagnostic fluid due to its noninvasive collection and potential for biomarker discovery. This study employs proteomic analysis to identify salivary biomarkers associated with Pd and to evaluate the impact of nonsurgical periodontal therapy (NSPT) on the salivary proteome. Comparative proteomic analysis was performed on saliva samples from periodontally healthy individuals (G1 group) and patients with advanced Pd (G2 group). For G2 patients, samples were collected both before and after NSPT. Mass spectrometry (MS) was used to identify differentially expressed proteins. Additionally, cell-free mitochondrial DNA (cf-mtDNA) was quantified as a marker of tissue damage and endogenous inflammation, and bacterial DNA as an indicator of microbial burden, to better characterize the inflammatory microenvironment. Proteomic profiling identified 66 salivary proteins differentially expressed in Pd patients at baseline compared to healthy controls, mainly associated with inflammation, immune response, oxidative stress, and extracellular matrix (ECM) degradation. These proteins significantly decreased following NSPT, correlating with improved clinical periodontal parameters. Notably, cf-mtDNA was elevated in Pd patients and decreased after treatment, mirroring the changes observed in bacterial DNA. Salivary proteome analysis revealed a distinct disease-associated protein signature in G2 group, supporting its potential as a noninvasive tool for diagnosis and monitoring of Pd patients. The post-NSPT shifts in protein expression further highlight the effectiveness of periodontal therapy in modulating inflammatory biomarkers. Future studies on larger cohorts are needed to validate these findings and advance saliva-based proteomics toward personalized periodontal care.