The aim of this systematic review is to investigate the literature to assess the effect of dental fluorosis on the Oral Health-Related Quality of Life (OHRQoL). Included studies were epidemiological investigations, clinical trials, or human studies that directly compared the impact on OHRQoL between individuals with dental fluorosis and those without, utilizing valid OHRQoL assessment tools. The searches were conducted up to March 2024 in databases, including PubMed, Scielo, LILACS, Scopus, Web of Science, Embase, and the Virtual Health Library. Additionally, gray literature sources such as Google Scholar, OpenGrey, Ibict/BDTD, and ProQuest were searched. Reference lists were also manually reviewed for potential eligible studies. The risk of bias in cohort studies was assessed using the Newcastle-Ottawa Scale (NOS), while its modified version was employed for cross-sectional studies. A narrative synthesis of the results was conducted. 16 studies were included in this Systematic Review. In total, 16,314 participants, aged 8 to 18, were assessed across the studies. Most of the included studies were cross-sectional, except for one cohort study. In assessing OHRQoL across different age groups and severities of dental fluorosis, the impact varied. A negative association between dental fluorosis and OHRQoL was found in 9 of the included studies, a positive association was found in 1 study, and no significative association was identified in 6 studies. Limitations in the included studies primarily pertained to cross-sectional designs, with significant issues such as the absence of sample size calculations, lack of non-response rate reporting, limited consideration of confounding factors, and substantial heterogeneity stemming from diverse diagnostic methods and assessment tools. The findings of the systematic review demonstrate a complex and varied relationship between dental fluorosis and OHRQoL in children and adolescents. These conclusions may have limitations in scientific evidence. The findings emphasize the need for further investigations to explore the intricate aspects of this relationship and identify contributing factors to varying outcomes. Dental caries preventive fluoridated measures might be indicated even if there would be a risk for mild dental fluorosis as the fluoridated public water. This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under number: CRD42020186552.