Background: Cancer patients who undergo allogeneic hematopoietic stem cell transplantation are among the most medically fragile patient populations with extreme demands for caregivers. Indeed, with earlier hospital discharges, the demands placed on caregivers continue to intensify. Moreover, an increased number of allogeneic hematopoietic stem cell transplantations are being performed worldwide, and this expensive procedure has significant economic consequences. Thus, the health and well-being of family caregivers have attracted widespread attention. Mobile health technology has been shown to deliver flexible, and time- and cost-sparing interventions to support family caregivers across the care trajectory. Objective: This protocol aims to leverage technology to deliver a novel caregiver-facing mobile health intervention named Roadmap 2.0. We will evaluate the effectiveness of Roadmap 2.0 in family caregivers of patients undergoing hematopoietic stem cell transplantation. Methods: The Roadmap 2.0 intervention will consist of a mobile randomized trial comparing a positive psychology intervention arm with a control arm in family caregiver-patient dyads. The primary outcome will be caregiver health-related quality of life, as assessed by the PROMIS Global Health scale at day 120 post-transplant. Secondary outcomes will include other PROMIS caregiver- and patient-reported outcomes, including companionship, self-efficacy for managing symptoms, self-efficacy for managing daily activities, positive affect and well-being, sleep disturbance, depression, and anxiety. Semistructured qualitative interviews will be conducted among participants at the completion of the study. We will also measure objective physiological markers (eg, sleep, activity, heart rate) through wearable wrist sensors and health care utilization data through electronic health records. Results: We plan to enroll 166 family caregiver-patient dyads for the full data analysis. The study has received Institutional Review Board approval as well as Code Review and Information Assurance approval from our health information technology services. Owing to the COVID-19 pandemic, the study has been briefly put on hold. However, recruitment began in August 2020. We have converted all recruitment, enrollment, and onboarding processes to be conducted remotely through video telehealth. Consent will be obtained electronically through the Roadmap 2.0 app. Conclusions: This mobile randomized trial will determine if positive psychology-based activities delivered through mobile health technology can improve caregiver health-related quality of life over a 16-week study period. This study will provide additional data on the effects of wearable wrist sensors on caregiver and patient self-report outcomes.