Background: to evaluate the effectiveness of different topical agents in biofilm disaggregation during non-surgical periodontal therapy. Methods: the search strategy was conducted according to the PRISMA 2020 on Pubmed, Cochrane Library, Scopus, and Web of Science, and it was registered in PROSPERO, ID: CRD42023474232. It included studies comparing non-surgical periodontal therapy (NSPT) with and without the application of topical agents for biofilm disruption. A risk of bias analysis, a qualitative analysis, and a quantitative analysis were performed. Results: out of 1583 records, 11 articles were included: 10 randomized clinical trials and one retrospective analysis. The total number of participants considered in the 11 articles included in the study was 386. The primary outcomes were probing pocket depth (PPD), clinical attachment level (CAL), and bleeding indices. The secondary outcomes were plaque indices, gingival recessions, and microbiological parameters. The meta-analysis revealed the following: [Weighted mean difference (WMD): −0.37; 95% confidence interval (CI) (−0.62, −0.12), heterogeneity I²: 79%, statistical significance p = 0.004]. Conclusions: the meta-analysis of probing pocket depth reduction (PPD) between baseline and follow-up at 3–6 months showed a statistically significant result in favor of sulfonated phenolics gel. The scientific evidence is still limited and heterogeneous; further randomized clinical trials are required.