This systematic review aims to identify and analyze the microbiological alterations caused by various therapeutic modalities for periodontal disease. The study critically evaluates current findings from English-language papers published between January 1, 2004, and May 7, 2024, in PubMed, Scopus, and Web of Science. A total of 5152 papers were initially identified, reducing to 475 after duplicate removal and title/abstract screening. The final analysis included 22 articles, focusing on the impact of treatments like scaling and root planing (SRP), probiotics, antibiotics, and advanced therapies on the oral microbiome. Key findings include: - Periodontitis alters the oral microbiome, increasing antibiotic resistance. - SRP, especially combined with minocycline, improves clinical outcomes by reducing harmful bacteria. - Comprehensive mechanical debridement with antibiotics, probiotics, and other adjunctive therapies enhances periodontal health. - Personalized treatment strategies and advanced microbial analyses are crucial for effective management and controlling antibiotic resistance. The review highlights the importance of understanding the microbiological changes induced by treatments to develop more individualized and potent therapeutic approaches. It also emphasizes the need for ongoing surveillance and routine maintenance to maintain long-term periodontal health.This systematic review aims to identify and analyze the microbiological alterations caused by various therapeutic modalities for periodontal disease. The study critically evaluates current findings from English-language papers published between January 1, 2004, and May 7, 2024, in PubMed, Scopus, and Web of Science. A total of 5152 papers were initially identified, reducing to 475 after duplicate removal and title/abstract screening. The final analysis included 22 articles, focusing on the impact of treatments like scaling and root planing (SRP), probiotics, antibiotics, and advanced therapies on the oral microbiome. Key findings include: - Periodontitis alters the oral microbiome, increasing antibiotic resistance. - SRP, especially combined with minocycline, improves clinical outcomes by reducing harmful bacteria. - Comprehensive mechanical debridement with antibiotics, probiotics, and other adjunctive therapies enhances periodontal health. - Personalized treatment strategies and advanced microbial analyses are crucial for effective management and controlling antibiotic resistance. The review highlights the importance of understanding the microbiological changes induced by treatments to develop more individualized and potent therapeutic approaches. It also emphasizes the need for ongoing surveillance and routine maintenance to maintain long-term periodontal health.