IntroductionThis study evaluated the impact of anti-inflammatory and analgesic agents on managing pain and sensitivity related to dental bleaching.MethodsA PROSPERO-registered systematic review (CRD42024528788) searched PubMed, Scopus, Web of Science, LILACS, EBSCOhost, LIVIVO, Embase, and Grey literature (Google Scholar) up to March 2024. From 3,185 articles screened, 16 placebo-controlled RCTs involving 823 patients were included. NSAIDs were the most commonly used drugs, with some studies incorporating corticosteroids. Risk of Bias (RoB) was assessed using Rob-2, and a meta-analysis evaluated mean differences and relative risks across subgroups. GRADE-pro assessed evidence certainty.ResultsFindings revealed no significant improvement in pain or sensitivity scores (VAS: p = 0.770; NRS: p = 0.980) or tooth sensitivity incidence (p = 0.750) compared to placebo. However, 1 hour post-bleaching, the intervention group showed a slight VAS score reduction (mean difference: -0.49, CI95% = -0.83 to -0.16; p = 0.004). Whitening results (Delta E: p = 0.140) and NSGU perception showed no differences, but the VITA scale slightly favored the placebo (p = 0.030). Ibuprofen or paracetamol-plus-codeine were the only that showed any clinical benefit.ConclusionsAnti-inflammatory or analgesic agents provided minimal benefit for controlling post-bleaching pain/sensitivity reducing 0.49-VAS-scores (clinically insignificant). There is a need to optimize pain management in dental bleaching, especially focusing on COX-2 selective NSAIDs.