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Fixed orthodontic treatment is commonly associated with pain and discomfort, particularly during the initial stages, which may influence patient adherence and satisfaction; however, a comprehensive synthesis of evidence, specifically focused on the adult population, remains limited. This systematic review aimed to evaluate pain and oral health-related quality of life (OHRQoL) in adult patients undergoing fixed orthodontic treatment. Electronic searches were conducted up to August 2025 across multiple databases, including PubMed®, Web of Science™, Scopus®, Google™ Scholar, PsycINFO®, EMBASE®, and the Cochrane Library, with no restrictions on publication date or language. Observational studies, randomized controlled trials (RCTs), and controlled clinical trials (CCTs) involving patients aged 18 years or older, treated with conventional fixed appliances, were included. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the RoB-2 and ROBINS-I tools. Meta-analysis was performed using RevMan 5.4 (The Cochrane Collaboration, The Nordic Cochrane Center, Copenhagen, Denmark), and the certainty of evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. A total of 14 studies involving 1,022 adult patients were included, comprising seven RCTs, three CCTs, three cohort studies, and one cross-sectional study. The mean age of participants ranged from 18.87 to 38 years, with a female predominance of approximately 61%. Pain intensity peaked at 24 hours post-activation, with Visual Analog Scale scores ranging widely from 19.5 to 56.7. Meta-analysis of two studies revealed a statistically and clinically significant reduction in pain from day 1 to week 1 (mean difference = 20.83, 95% confidence interval: 11.70 to 29.97, p < 0.00001, I² = 67%), with pain continuing to decline over subsequent weeks. OHRQoL, primarily measured using the Oral Health Impact Profile-14, showed initial impairment, followed by significant improvement over time. However, the overall certainty of evidence for both outcomes was rated as very low to low. In conclusion, fixed orthodontic treatment in adult patients is consistently associated with moderate-to-high pain levels that peak around 24 hours and decrease significantly within the first week, while OHRQoL follows a parallel pattern of initial decline, followed by measurable improvement within the first month. Clinicians may use these findings to counsel adult patients and set realistic expectations regarding the transient nature of initial discomfort. Given the very low to low certainty of evidence, there is an urgent need for more well-designed longitudinal studies, with standardized outcome assessment time points and reporting metrics, to strengthen the evidence base.