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The Harlem Children’s Zone (HCZ)® is a nonprofit organization that provides a comprehensive set of free programs to address the social, health, and educational development of children in Central Harlem—a New York City neighborhood with a child poverty rate that is more than double the national average. This study assessed the impact of Healthy Harlem, a comprehensive program aimed at promoting healthy lifestyles. All students attending HCZ after-school programs are exposed to the Prevention component, which includes physical activity, healthy snacks, nutrition education lessons, and parent workshops. Middle and high school students who are overweight or obese also participate in Get Fit, an intensive, 12-week program in which students identify and work on specific goals for improving their eating and/or physical activity habits. The study examined impacts of Healthy Harlem on students’ nutrition-related knowledge and attitudes, perceived social support for healthy eating and physical activity, fitness, and body-mass index (BMI). The findings provide strong evidence that in its first three years of implementation, Healthy Harlem has made significant contributions to promoting healthy lifestyles among HCZ students.