Adolescent health and well-being are abysmal due to low and declining physical activity rates, increasing mental health problems such as anxiety and depression, and minimal opportunities to engage in meaningful social experiences. Adolescents who live in communities that are underserved face greater risks for experiencing health disparities including lack of access to quality healthcare, nutritious foods, social support, and educational opportunities and safety. Existing efforts have been developed and implemented to address these challenges with limited success. A university-school-community approach to adolescent well-being may offer innovative strategies to improve and enhance the well-being of adolescents from communities that are underserved. A university-school-community partnership was established to implement innovative health and well-being programming for Indiana youth at a charter school. This school was founded by Purdue University to engage and provide at-risk students with the preparation for future opportunities in higher education. In addition to strategic partnerships, this partnership utilizes a prevention science approach to mitigate youth well-being risks and offers positive-oriented experiences to address them. University partners have collaborated with community organizations and relevant community partners to implement such efforts. This article outlines a collaborative evidence-based model to build sustainable well-being efforts in other schools and communities.