Background: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread wildly across the world. In March of 2020, almost all kindergarten through 12th grade (K-12) schools were closed in the United States in an urgent attempt to curb the pandemic in the absence of effective therapeutics or vaccination. Thirteen months since then, schools remain partially closed. Accumulated evidence suggests that children and adolescents are not the primary facilitators of transmission, limiting the restrictive effects of school closures on disease transmission. The negative effects of school closures on K-12 students need to be systematically reviewed.Methods: Following the guideline of Preferred Reporting Items for Systematic Reviews and Meta-analyzes, a comprehensive literature search from PubMed, EMBASE, Cochrane Library, Scopus, and Web of Science regarding school closures and its impact on K-12 students was conducted. The primary outcomes included the impact of school closures on the mitigation of the pandemic and the resulting public health concerns of K-12 students.Results: Prolonged school closures possessed negative effects on K-12 students' physical, mental, and social well-being and reduced the number of health and social workers, hindering the reopening of the country.Conclusions: School closures were over-weighted against the mitigation of coronavirus disease 2019 (COVID-19) transmission. A safe reopening of all K-12 schools in the United States should be of top priority.Abbreviations: COVID-19 = coronavirus disease 2019, K-12 = kindergarten through 12th grade, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.