Aim To answer the following PICOS question: in adult patients with periodontitis, which is the efficacy of adjunctive locally delivered antimicrobials, in comparison with subgingival debridement alone or plus a placebo, in terms of probing pocket depth (PPD) reduction, in randomized clinical trials with at least 6 months of follow‐up. Material and methods A systematic search was conducted: 59 papers, reporting 50 different studies, were included. Data on clinical outcome variables changes were pooled and analysed using weighted mean differences (WMDs) and 95% confidence intervals (CI), and prediction intervals (PI), in case of significant heterogeneity. Results Statistically significant differences were observed, in 6‐ to 9‐month studies, for PPD (WMD = 0.365, 95% CI 0.262; 0.468, PI −0.29; 1.01) and clinical attachment level (CAL) (WMD = 0.263, 95% CI 0.123; 0.403, PI −0.43; 0.96). For long‐term studies, significant differences were observed for PPD (WMD = 0.190, 95% CI 0.059; 0.321), but not for CAL. For adverse events, no differences were observed. Results were affected by study design (split‐mouth versus parallel studies) and assessment (full‐ or partial‐mouth), as well as by the formulation tested. Conclusions The use adjunctive locally delivered antimicrobials in periodontitis therapy results in statistically significant benefits in clinical outcomes, without relevant side effects.