Background We conducted in-depth interviews to characterize reasons for COVID-19 vaccine hesitancy in emergency department (ED) patients and developed messaging platforms that may address their concerns. In this trial we seek to determine whether provision of these COVID-19 vaccine messaging platforms in EDs will be associated with greater COVID-19 vaccine acceptance and uptake in unvaccinated ED patients. Methods This is a cluster-randomized controlled trial (RCT) evaluating our COVID-19 vaccine messaging platforms in seven hospital EDs (mix of academic, community, and safety-net EDs) in four US cities. Within each study site, we randomized 30 one-week periods to the intervention and 30 one-week periods to the control. Adult patients who have not received a COVID-19 vaccine are eligible with these exclusions: 1) major trauma, intoxication, altered mental status, or critical illness; 2) incarceration; 3) psychiatric chief complaint; and 4) suspicion of acute COVID-19 illness. Participants receive an orally administered Intake survey. During intervention weeks participants then receive three COVID-19 vaccine messaging platforms (4-minute video, one-page informational flyer and a brief, scripted face-to-face message delivered by ED physicians and nurses); patients enrolled during non-intervention weeks do not receive these platforms. Approximately an hour after intake surveys, participants receive a Vaccine Acceptance survey during which the primary outcome of acceptance of the COVID-19 vaccine in the ED is ascertained. The other primary outcome of receipt of a COVID-19 vaccine within 32 days is ascertained by electronic health record review and phone follow-up. To determine whether provision of vaccine messaging platforms is associated with a 7% increase in vaccine acceptance and uptake, we will need to enroll 1290 patients. Discussion Highlighting the difficulties of trial implementation during the COVID-19 pandemic in acute care settings, our novel trial will lay the groundwork for delivery of public health interventions to vulnerable populations whose only health care access occurs in EDs. Trial Status: We began enrollment in December 2021 and expect to continue through 2022. Conclusions Toward addressing vaccine hesitancy in vulnerable populations who seek care in EDs, our cluster-RCT will determine whether implementation of vaccine messaging platforms is associated with greater COVID-19 vaccine acceptance and uptake in unvaccinated ED patients.