Introduction Cold atmospheric pressure plasma (CAPP) has emerged as a promising nonthermal technology for antimicrobial disinfection and tissue modulation in dentistry. Its reactive oxygen and nitrogen species (RONS) facilitate the destruction of microorganisms, the disruption of biofilms, and the biomodulation of cells and tissues without causing thermal harm. The lack of translation into clinical practice despite the large number of in vitro investigations calls for a thorough synthesis of the available data. Objective To systematically evaluate the efficacy and safety of CAPP across dental applications based on preclinical (in vitro and animal) and clinical studies. Materials and Methods This review was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420251154333) and adhered to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. A comprehensive search was conducted in PubMed, MEDLINE, Scopus, Cochrane CENTRAL, and Web of Science. Inclusion criteria encompassed in vitro, ex vivo, animal, and human studies employing CAPP or plasma‐activated liquids (PALs) for dental applications. Outcomes included antimicrobial efficacy, remineralization, bond strength, wound healing, and safety. Results Nineteen studies met the inclusion criteria. Consistent antibacterial, remineralizing, and bonding‐enhancing effects were shown in in vitro tests, along with significant increases in fibroblast proliferation and wound healing capability. Long‐term exposure safety and a decrease in alveolar bone loss, peri‐implant bacterial load, and periodontal inflammation were validated by in vivo investigations. No cytotoxic or carcinogenic effects were reported. Conclusions Evidence from included studies, which were predominantly preclinical, suggests that CAPP demonstrates antimicrobial, bonding, remineralization, and regenerative potential with a favorable safety profile. However, clinical evidence is limited to a single short‐term randomized trial. Therefore, conclusions regarding routine clinical application remain preliminary, and further well‐designed clinical studies are required.
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