Objectives <p>Systematically evaluate the clinical efficacy of systemically administered non-steroidal anti-inflammatory drugs (NSAIDs) as an adjunct to scaling and root planing (SRP) for periodontitis, assess the therapeutic effects of different drugs, and identify the most effective treatment regimen.</p> Materials and methods <p>This study is registered in PROSPERO under trial No. CRD420250651756. Randomized controlled trials (RCTs) examining systemic NSAIDs as SRP adjuncts were identified through systematic searches of PubMed, Embase, Web of Science, Cochrane Library and CNKI databases. Eligible studies were screened, followed by data extraction and risk-of-bias assessment using Cochrane criteria. Efficacy was assessed through changes in probing depth (PD) and clinical attachment loss (CAL). Statistical analyses were performed using Stata 18.0, and R 4.4.3 software.</p> Results <p>Thirteen RCTs involving 549 patients met inclusion criteria. The results of the Network meta-analysis (NMA) identified that, when NSAIDs are used as an adjuvant treatment for periodontitis, compared with using only SRP to treat periodontitis, ibuprofen + SRP [MD = 0.58, 95% CI (0.31, 0.85)] shows the most significant efficacy in improving PD and CAL after 1 - month follow - up. At 3 months, the ibuprofen-doxycycline combination [MD = 1.70, 95% CI (1.16, 2.24)] and omega-3 polyunsaturated fatty acids (PUFAs) combined with aspirin [MD = 0.82, 95% CI (0.57, 1.07)] demonstrated superior efficacy versus monotherapies.</p> Conclusions <p>Current evidence suggests that systemic administration of NSAIDs as an adjunct to periodontal baseline therapy may provide clinically significant benefits in periodontitis management. However, further well-designed randomized controlled trials with larger sample sizes are required to validate and refine this conclusion.</p>