ABSTRACT Background: The objective is to compare the impact of clear aligner treatment (CAT) versus conventional fixed appliance treatment (FAT) on oral health-related quality of life (OHRQoL) among adults at five-time points: pretreatment (T0), 1 week (T1), 1 month after (T2), and 6 months after (T3) treatment initiation, and in the long-term follow-up (T4). Materials and Methods: Search terms were based on Medical Subject Headings (MeSH) and non-MeSH. Potentially eligible studies compared OHRQoL in clear aligner (CA) and fixed appliance (FA) patients. In February 2023, Scopus, Web of Science, Cochrane, and PubMed were searched for published studies. Nine out of 94 shortlisted papers were eligible for a systematic review. Of these nine papers, five studies were considered for a meta-analysis. Results: At T0, CA and FA patients had similar oral health impact profile (OHIP)-14 questionnaire scores with a standard mean difference (SMD) of 0.105 (confidence interval [CI]:−1.029–1.48).The SMD of the OHRQoL related to T1, T2, and T3 was −3.119 (CI:−0.145, 0.355), −1.527 (CI:−5.597, −0.64), and− 2.331 (CI:−1.906, −1.148).T4 showed no difference between groups (SMD = 0.007, CI: CI:−4.286, −0.376). Regarding the OHIP-14 domains, functional limitations remained consistent in both groups across all time intervals. Psychological discomfort exhibited a notable difference only at T2. Throughout the treatment, CAT showed significantly lower levels of physical, psychological, and social disability, as well as handicap, though these differences did not persist beyond T4. Notably, physical pain was the sole domain that remained elevated in the FAT group up to T4. Conclusion: During the 1st day of the orthodontic treatment, both the CA and FA groups had comparable OHRQoL statuses. However, as time passed, the CA group notably improved their OHRQoL compared to the FA group. Interestingly, after a year or the completion of treatment, both groups eventually reached similar OHRQoL levels. Nevertheless, it is worth noting that FA patients continued to experience more physical pain even a year later.