Schools are an ideal setting to implement physical activity programs targeted at youths’ learning and intellectual abilities, as exercise has been associated with improvement in cognitive skills and academic proficiency. A systematic review of the literature was performed to examine the effects of school-based physical activity interventions on academic achievement and cognitive outcomes. A search for relevant papers was carried out on PubMed/Medline, Scopus and Google Scholar. Only quasi-experimental and experimental studies were included, if focused on school-based physical activity interventions targeting 3 to 18 year-old healthy pupils, and designed to establish a relationship between exercise performed in a school setting and cognitive/academic performance. Thirty-one papers were retrieved by the search, reporting the findings of twenty-eight school-based physical activity interventions. Most of the included studies were published in the past five years. A large majority of the studies showed positive results in terms of academic achievement and, above all, cognitive skills. In the recent years, the number of studies on school-based physical interventions aimed to establish a relationship between physical activity performed in school setting and cognitive/academic outcomes significantly increased, as well as high quality assessments and designs. This review highlights the effectiveness of school-based physical activity interventions on academic achievement and, above all, on youths’ cognitive performance. Some interesting findings come from studies assessing brain functional changes, from interventions targeting culturally diverse or low-income samples, and from interventions where physical activity is in the form of active videogames.