Background: Periodontitis is a chronic inflammatory disease characterized by a dysbiotic oral microbiome that leads to progressive periodontal tissue destruction. Current treatment primarily relies on scaling and root planing (SRP); however, this approach does not always completely eliminate pathogenic microorganisms or adequately modulate the host inflammatory response. Cold atmospheric plasma (CAP) generates reactive oxygen and nitrogen species (RONS) with potential antimicrobial, antibiofilm, and immunomodulatory properties, making it a promising adjunctive therapeutic modality for the management of periodontitis. Literature Search Strategy: A comprehensive literature search was conducted using PubMed/MEDLINE, Scopus, Web of Science, and Embase to identify relevant studies published between January 2000 and June 2025. The search included in vitro, in vivo, and clinical studies evaluating the antimicrobial, immunomodulatory, and regenerative effects of CAP in periodontitis and related periodontal models. Reference lists of relevant articles were also manually screened to identify additional eligible studies. Objectives: This review aims to provide a comprehensive overview of the antimicrobial and immunomodulatory effects of CAP on periodontitis and to evaluate its potential as an adjunctive treatment modality. Furthermore, the review examines the regenerative potential and underlying mechanisms of CAP, while also addressing its clinical safety and biocompatibility. Key Findings: Preclinical evidence indicates that CAP reduces bacterial viability, disrupts biofilm architecture, and modulates host immune responses through RONS-mediated signaling pathways. In animal models of periodontitis, CAP has been shown to enhance markers of periodontal tissue repair, reduce the expression of pro-inflammatory cytokines, increase LC3-associated phagocytosis in macrophages, and accelerate wound healing. Clinical studies evaluating CAP as an adjunct to SRP have reported improvements in clinical attachment level (CAL) and reductions in the recolonization of periodontal pathogens. Nevertheless, substantial heterogeneity in CAP treatment parameters and a lack of long-term safety and efficacy data limit direct comparisons across studies and highlight the need for further well-designed clinical investigations. Conclusions: CAP appears to be a potentially useful adjunct to SRP in the management of periodontitis. Current preclinical evidence demonstrates significant antimicrobial, immunomodulatory, and regenerative effects; however, clinical evidence remains limited. Further high-quality clinical trials are required to validate these findings, establish standardized treatment protocols, optimize therapeutic parameters, and facilitate the development of regulatory frameworks for clinical implementation.