Background: Fascioliasis is an animal parasitic infection that can infect humans and be a source of significant morbidity. The World Health Organization lists human fascioliasis as a neglected tropical disease, but the worldwide prevalence of fascioliasis data is unknown. We aimed to estimate the global prevalence of human fascioliasis.Methods: We performed a systematic review and prevalence meta-analysis. We used the following inclusion criteria: articles published in the English or Spanish languages from December 1985 to January 2021 and studies assessing the annual prevalence of Fasciola in the general population with an appropriate diagnostic methodology, including longitudinal studies, prospective and retrospective cohorts, case series, and randomized clinical trials (RCTs). Filters were used to limit results to human studies. Two reviewers independently reviewed the selected studies for methodological quality, performing critical standard measures from JBI SUMARI. A random-effects model was performed of the summary extracted data on annual prevalence rates. We reported the estimates according to the GATHER statement.Results: 5,617 studies were screened for eligibility. Fifty-one studies from 14 countries, including 149,704 patients and 3,913 cases, were selected. The meta-analysis revealed an annual pooled prevalence of 2.3% [95% confidence interval (CI): 1.5–3.7; I2=100%; T2=2.89]. The annual prevalence rates in South America, Africa, Asia, and Europe were 5.5%, 4.1%, 1%, and 0.6%, respectively. The highest annual prevalence rates were found in Bolivia (8.4%), Peru (7.8%), Ethiopia (4.2%), and Egypt (4%). Subgroup analysis showed increased prevalence in children when Fas2-ELISA was used as a diagnostic method. In a metaregression, countries with known endemicity were associated with higher prevalence rates, while large studies were associated with lower prevalence rates.Conclusion: The estimated annual prevalence of human fascioliasis is higher than previously reported. Study findings support that fascioliasis continues to be a globally neglected tropical disease. Strengthening epidemiological surveillance and implementing measures to control and treat fascioliasis is imperative in the most affected areas.Funding: None to declare. Ethical Approval: We declare no competing interests related to this work. Dr. Sillau reported receiving grants from the Alzheimer's Association, the Benign Essential Blepharospasm Research Foundation, the Colorado Department of Public Health, the Davis Phinney Foundation, the Hewitt Family Foundation, the Michael J. Fox Foundation, the National Institutes of Health, the National Institute of Nursing Research, the Patient-Centered Outcomes Research Institute, and the Rocky Mountain Alzheimer's Disease Center outside the submitted work. Dr. Henao-Martínez reported being the recipient of a K12-clinical trial award as a co-principal investigator for the Expanded Access IND Program (EAP) to provide the Yellow Fever vaccine (Stamaril) to Persons in the United States outside the submitted work. No other disclosures were reported.