The relationship between naturally fluoridated groundwater and dental fluorosis has received large attention from researchers around the world. Despite recognition that several factors influence this relationship, there is a lack of systematic studies analyzing the heterogeneity of these results. To fill such a gap, this study performs a systematic review and meta-analysis to understand which factors influence this relationship and how. Selected studies were sampled between 2007 and 2017 from Web of Science, PubMed, Google Scholar and Scopus using keywords and Boolean operators. Results of the systematic review show that dental fluorosis affects individuals of all ages, with the highest prevalence below 11, while the impact of other factors (gender, environmental conditions, diet and dental caries) was inconclusive. Meta-regression analysis, based on information collected through systematic review, indicates that both fluoride in drinking water and temperature influence dental fluorosis significantly and that these studies might be affected by publication bias. Findings show that fluoride negatively affects people's health in less developed countries. The conclusions discuss policy tools and technological innovations that could reduce fluoride levels below that of the WHO (<1.5 mg/L).