Background and Objective: Elements of internal (e.g., effectiveness) and external (e.g., implementation) validities of the World Health Organization’s Health-Promoting Schools (HPS-WHO) in Latin American countries are still unknown. This study aimed to synthesize information on internal and external validities (using the RE-AIM model: reach, effectiveness/efficacy, adoption, implementation, and maintenance) of interventions based on the EPS-WHO in Latin American schools. Methods: This systematic review follows the PRISMA guidelines (PROSPERO: CRD42020168069). Searches were performed in May 2020 in eight databases (Medline, LILACS, Web of Science, Scopus, PsycINFO, Eric, SciELO, and Cochrane), five gray literature websites, eight institutional websites, and similar reviews. Eligible studies were interventions with strategies that address the HPS-WHO model and included students aged 5-18 years of schools from Latin American countries. A validated 21-item checklist was used to calculate RE-AIM scores according to the interventions’ characteristics (age groups, country, and theoretical model adopted). Results: Initially, 2347 titles were reached; 58 studies were eligible, representing 23 interventions from seven countries: Brazil (n=12), Mexico (n=5), Peru (n=2), Chile, Costa Rica, Ecuador, and Uruguay (1 study each). “Reach” and “Effectiveness” were reported in all interventions. “Adoption”, “Implementation”, and “Maintenance” were reported in 91.3%, 82.6%, and 56.5% of interventions, respectively. The RE-AIM total score was low (0-7 points) in 12 interventions, moderate (8-14 points) in 10, and high (15-21 points) in one. Better RE-AIM total scores were observed in studies with the following characteristics: with adolescents, the HPS-WHO as the theoretical framework of strategies, and from Brazil. Conclusions: We found a large number of interventions based on HPS-WHO in Latin America, but most of them had limited reporting, especially on external validity. Improving these elements is mandatory, which may guide research and practice of effective, scale-up, culturally adapted HPS-WHO strategies in countries from the region.