Diabetes is a costly epidemic in the United States associated with both health and economic consequences. These consequences can be mitigated by participation in structured lifestyle change programs such as the National Diabetes Prevention Program (DPP) led by the Centers for Disease Control and Prevention. Mississippi consistently has among the highest rates of diabetes and prediabetes nationally. Implementing the National DPP through large health care systems can increase reach and accessibility for populations at the highest risk for diabetes. Translational research on the National DPP in Mississippi has not been studied. This study aims to evaluate the implementation and impact of the National DPP delivered using telehealth modalities at the University of Mississippi Medical Center in Jackson, Mississippi. An effectiveness-implementation hybrid type III research design is proposed. The study design is guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework and the Practical, Robust Implementation and Sustainability Model. Participants are being recruited via provider referral, and the DPP is being delivered by trained lifestyle coaches. Study participants include adult (≥18 years) patients eligible for the DPP with at least 1 encounter at 1 of 3 ambulatory clinic specialties (lifestyle medicine, family medicine, and internal medicine) between January 2019 and December 2023. The National DPP eligibility criteria include a BMI ≥25 kg/m2 and hemoglobin A1c between 5.7% and 6.4%. The University of Mississippi Medical Center criteria include Medicare or Medicaid beneficiaries. The University of Mississippi Medical Center's a priori implementation plan was developed using the Consolidated Framework for Implementation Research and includes 23 discrete strategies. The primary aim will use an embedded mixed method process analysis to identify and mitigate challenges to implementation. The secondary aim will use a nonrandomized quasi-experimental design to assess the comparative effectiveness of the DPP on health care expenditures. A propensity score matching method will be implemented to compare case subjects to control subjects. The primary outcomes include patient referrals, participant enrollment, retention, engagement, the incidence of diabetes, and health care resource use and costs. At baseline, of the 26,151 patients across 3 ambulatory clinic specialties, 1010 (3.9%) had prediabetes and were eligible for the National DPP. Of the 1010 patients, more than half (n=562, 55.6%) were aged 65 years or older, 79.5% (n=803) were Medicare beneficiaries, 65.9% (n=666) were female, and 70.8% (n=715) were obese. This is the first translational study of the National DPP in Mississippi. The findings will inform implementation strategies impacting the uptake and sustainability of the National DPP delivered in an academic medical setting using distance learning and telehealth modalities. ClinicalTrials.gov NCT04822480; https://clinicaltrials.gov/study/NCT03622580. DERR1-10.2196/50183.