Background: Afterschool programs (ASPs) have been identified as ideal settings where children can accumulate a significant portion of their total daily physical activity (PA). The purpose of the current study was to assess the effectiveness of the Active Science program in promoting PA and science learning in different site locations across the U.S. Methods: Participants were 72 children (35 females, mean age = 9.2 years, standard deviation [SD] = 0.9) from five YMCA afterschool childcare sites located in five states. The 6-week Active Science program was implemented twice/week for 60 min at a site. The participants completed 30 min of PA followed by a science lesson delivered through the Active Science Mobile App. Sites were randomly assigned to Active Science and the control (i.e., regular ASP). After 6 weeks, the sites switched to enable both groups to receive the intervention. Science tests and accelerometers were used to measure science performance, steps, and moderate-to-vigorous PA (MVPA) minutes. The pre- and post-results were compared and analyzed by ANOVA. Results: For PA, participants had significantly higher steps/30 min when they completed the Active Science program compared to the traditional ASP, mean = 1826, SD = 571, mean = 685, SD = 161, respectively, F (1,55) = 280, P < 0.001. Significant differences were found with MVPA%, mean = 38.16%, SD = 20.05%, mean = 30.03%, SD = 14.83%, respectively, F (1,55) = 44.8, P < 0.001. For science learning, the pre- and post-improvement was significant for the Active Science group, P < 0.001. Average science test score for pre- and post-tests were mean = 57.14, SD = 20.56, and mean = 75.24, SD = 15.61, respectively. For the control group, the pre- and post-improvement was not significant, P > 0.05. Conclusion: The results supported that children had significantly higher PA levels and improved students’ science scores when they participated in Active Science.