The health consequences of excessive screen media use in children and adolescents are increasingly being recognized; however, the association between screen media use and academic performance remains to be elucidated. To estimate the association of time spent on screen-based activities with specific academic performance areas in children and adolescents and to examine this association separately in these populations. MEDLINE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, and ERIC were searched from database inception through September 2018. Cross-sectional studies of the association between time or frequency of screen media use and academic performance in children and adolescents were independently screened by 2 researchers. A total of 5599 studies, published between 1958 and 2018 from 23 countries, were identified. Data were processed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Random-effects models were used to estimate the pooled effect size (ES). Academic performance areas included composite scores, language, and mathematics. Screen media measurements included time or frequency of computer, internet, mobile phone, television, video game, and overall screen media use. In total, 58 cross-sectional studies (1.0%) of 5599 articles were included in the systematic review, of which 30 (52%) were included in the meta-analysis. The systematic review studies involved 480 479 participants aged 4 to 18 years, ranging from 30 to 192 000 people per study, and the meta-analysis studies involved 106 653 total participants, ranging from 70 to 42 041 people per study. Across studies, the amount of time spent on overall screen media use was not associated with academic performance (ES = -0.29; 95% CI, -0.65 to 0.08). Individually, television viewing was inversely associated with composite academic performance scores (ES = -0.19; 95% CI, -0.29 to -0.09), language (ES = -0.18; 95% CI, -0.36 to -0.01), and mathematics (ES = -0.25; 95% CI, -0.33 to -0.16). Video game playing was inversely associated with composite scores (ES = -0.15; 95% CI, -0.22 to -0.08). Subgroup analyses found that television viewing was inversely associated with language only in children (ES = -0.20; 95% CI, -0.26 to -0.15), whereas both television viewing (ES = -0.19; 95% CI, -0.30 to -0.07) and video game playing (ES = -0.16; 95% CI, -0.24 to -0.09) were inversely associated with composite scores only in adolescents. Findings from this study suggest that each screen-based activity should be analyzed individually for its association with academic performance, particularly television viewing and video game playing, which appeared to be the activities most negatively associated with academic outcomes. Education and public health professionals should consider supervision and reduction to improve the academic performance of children and adolescents exposed to these activities.