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Abstract Background The National Diabetes Prevention Program (National DPP) is rapidly expanding in an effort to help those at high risk of type 2 diabetes prevent or delay the disease. In 2012, the Centers for Disease Control and Prevention funded six national organizations to scale and sustain multistate delivery of the National DPP lifestyle change intervention (LCI). This study aims to describe reach, adoption, and maintenance during the 4-year funding period and to assess associations between site-level factors and program effectiveness regarding participant attendance and participation duration. Methods The Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework was used to guide the evaluation from October 2012 to September 2016. Multilevel linear regressions were used to examine associations between participant-level demographics and site-level strategies and number of sessions attended, attendance in months 7–12, and duration of participation. Results The six funded national organizations increased the number of participating sites from 68 in 2012 to 164 by 2016 across 38 states and enrolled 14,876 eligible participants. By September 2016, coverage for the National DPP LCI was secured for 42 private insurers and 7 public payers. Nearly 200 employers were recruited to offer the LCI on site to their employees. Site-level strategies significantly associated with higher overall attendance, attendance in months 7–12, and longer participation duration included using self-referral or word of mouth as a recruitment strategy, providing non-monetary incentives for participation, and using cultural adaptations to address participants’ needs. Sites receiving referrals from healthcare providers or health systems also had higher attendance in months 7–12 and longer participation duration. At the participant level, better outcomes were achieved among those aged 65+ (vs. 18–44 or 45–64), those who were overweight (vs. obesity), those who were non-Hispanic white (vs. non-Hispanic black or multiracial/other races), and those eligible based on a blood test or history of gestational diabetes mellitus (vs. screening positive on a risk test). Conclusions In a time of rapid dissemination of the National DPP LCI the findings of this evaluation can be used to enhance program implementation and translate lessons learned to similar organizations and settings.