Background: After-school programs (ASPs) play a crucial role in supplementing the present school day. However, implementing ASPs in the urban environment and among adolescents (grades 6-12) poses unique challenges. The purpose of this study was to conduct a systematic literature review to identify evidence-based barriers and facilitators to after-school programming in urban school environments. Methods: Twenty-five publications meeting the authors' inclusion criteria over the past 10 years were reviewed and synthesized. Results: Results demonstrated that the demand for ASPs is increasing. Several barriers, including staffing, funding, resources, transportation, and space, were identified. Specific challenges regarding the implementation of ASPs for adolescents in urban areas were also determined. A number of best practices were identified along with benefits for academic engagement and social-emotional coping skill development. Conclusions: Efforts to address these specific barriers and facilitators to ASP implementation may contribute to improving broader health and academic outcomes among adolescent youth.