Abstract Background: Higher rates of physical inactivity and comorbid conditions are reported in Hispanic and Black cancer patients receiving chemotherapy, compared to their White counterparts. Despite the beneficial effect of exercise training for cancer patients, rates of participation in clinical cancer trials are low among disadvantaged and racial and ethnic minority groups. This is possibly due to more barriers and less access to exercise training. Therefore, there is a crucial need for better understanding of how to apply exercise interventions using novel, accessible, and cost-effective home-based exercise approaches for Hispanic and Black communities, particularly during chemotherapy. In this study, we will examine the effect of supervised and unsupervised exercise on minutes of physical activity among Hispanic and Black cancer patients undergoing chemotherapy for breast, colorectal, and prostate cancer. Methods: The THRIVE trial is an 8-month prospective, three-arm study of 135 patients who are randomized in a 1:1:1 fashion to a supervised exercise intervention (SUP), unsupervised exercise (UNSUP), or an attention control group. Eligible patients include those with early-stage breast, colorectal, or prostate cancer, planning to receive chemotherapy, are sedentary, overweight or obese, and self-identifying as Hispanic or Black. Patients randomized to the SUP group participate in a home-based 16-week periodized aerobic and resistance exercise program performed three days per week, supervised through video conference technology. Patients randomized to the UNSUP group participate in an unsupervised 16-week, telehealth-based, periodized aerobic and resistance exercise program performed three days per week using the same exercise prescription parameters as the SUP group. The attention control group receive a 16-week home-based stretching program. The primary outcome is changes in minutes of physical activity assessed by 7-day accelerometry at month 4. Secondary outcomes include cardiovascular risk factors, patient-reported outcomes, and physical function. Outcome measures are tested at baseline, post-intervention at month 4, and after a non-intervention follow-up period at month 8. Discussion: The THRIVE trial is the first study to employ a novel and potentially achievable exercise intervention for a minority population receiving chemotherapy. In addition, this study utilizes an intervention approach to investigate the biological and behavioral mechanisms underlying exercise participation in these cancer patients. Results from this study will guide and inform large randomized controlled trials to test the effect of home-based exercise on treatment outcomes and comorbid disease risk in minority patients with cancer undergoing chemotherapy. Citation Format: Huimin Yan, Noelle Merchant, Ashley Desameau, Cherardi NeiraViscue, Paola Gonzalo-Encabo, Dong-Woo Kang, Rebekah L. Wilson, Mary K. Norris, Danny Nguyen, Daniel Gundersen, Laura L. Hayman, Rachel A. Freedman, Timothy Rebbeck, Christina M. Dieli-Conwright. Testing Home-based Exercise Strategies in Underserved Minority Cancer Patients Undergoing Chemotherapy (THRIVE) Trial: A study protocol [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C109.