Background and Objectives: The impact of orthodontic appliances on oral health-related quality of life (OHRQoL) has gained increasing attention, particularly in relation to patient-centered outcomes. Clear aligners (CAs) are often perceived as more comfortable than fixed appliances (FAs), although evidence remains limited and heterogeneous. This systematic review and meta-analysis aimed to compare the effects of CAs and FAs on OHRQoL in patients with Angle class I malocclusion and to further evaluate the reliability of the findings using trial sequential analysis (TSA). Materials and Methods: This review followed PRISMA guidelines and was registered in PROSPERO (CRD420251051003). A comprehensive search of PubMed, Scopus, Web of Science, Embase, and Cochrane CENTRAL was conducted. Only randomized controlled trials comparing CAs and FAs and reporting OHRQoL outcomes (OHIP-14) were included. Random-effects meta-analyses were performed on early changes in OHRQoL. TSA was applied to control for type I and II errors and to evaluate the sufficiency of the cumulative evidence. Results: Two randomized controlled trials (n = 74) were included in the quantitative synthesis. Both treatments were associated with a transient deterioration in OHRQoL after appliance placement. Meta-analysis showed statistically significant improvements favoring CAs in psychological discomfort (p = 0.007) and psychological disability (p < 0.001), while no significant differences were observed for other domains or for overall OHRQoL. Exploratory TSA suggested an early signal in favor of psychological outcomes, with the cumulative Z-curve crossing the monitoring boundary; however, given the very small number of included trials, these findings should be regarded as preliminary and hypothesis-generating rather than confirmatory. In contrast, for most other outcomes, the required information size was not reached and results remained inconclusive. For handicap, TSA suggested that a clinically relevant difference is unlikely. Conclusions: Clear aligners may provide a modest short-term advantage over fixed appliances in psychological aspects of OHRQoL, while no consistent differences are observed in physical or overall domains, based on very limited evidence. TSA suggests a preliminary signal in psychological outcomes but highlights insufficient evidence for most other domains. These results should be interpreted with caution, and further high-quality randomized trials are needed.