UNLABELLED: This randomized double-blind placebo-controlled clinical trial aimed to evaluate the adjunctive use of Streptococcus salivarius M18 probiotic lozenges in the treatment of periodontitis. Following non-surgical periodontal therapy (NSPT), 55 participants with stage III or IV periodontitis were administered either S. salivarius M18 lozenges (test group) or a placebo for 12 weeks. Clinical assessments, including pocket probing depth (PPD), clinical attachment loss (CAL), bleeding on probing (BoP), and plaque index (PI), were performed at baseline (before treatment), immediately after treatment, and during post-treatment follow-ups at 12 and 24 weeks. Microbial analysis was conducted on the subgingival plaque samples collected. The test group demonstrated significantly improved PPD, BoP, and PI compared to the placebo group at post-treatment follow-ups, although no significant difference was observed in CAL. Microbiological analysis revealed a reduction in periodontal pathogens or a shift in the subgingival microbiota toward a decreased pathogenic profile in the test group. This trial is the first to demonstrate the safety and efficacy of S. salivarius M18 as an adjunctive treatment for periodontitis, supporting its potential for broader clinical use in managing periodontal health. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04363-w.