ImportanceLarge segments of the US population’s primary health care access occurs in emergency departments (EDs). These groups have disproportionately high COVID-19 vaccine hesitancy and lower vaccine uptake.ObjectiveTo determine whether provision of COVID-19 vaccine messaging platforms in EDs increases COVID-19 vaccine acceptance and uptake in unvaccinated patients.Design, Setting, and ParticipantsThis prospective cluster randomized clinical trial was conducted at 7 hospital EDs in 4 US cities from December 6, 2021, to July 28, 2022. Noncritically ill adult patients who had not previously received COVID-19 vaccines were enrolled.InterventionsA 3-pronged COVID-19 vaccine messaging platform (an English- or Spanish-language 4-minute video; a 1-page informational flyer; and a brief, scripted message from an ED physician or nurse) was delivered during patient waiting times.Main Outcomes and MeasuresThe 2 primary outcomes were (1) COVID-19 vaccine acceptance, assessed by survey responses in the ED, and (2) receipt of a COVID-19 vaccine within 30 days, ascertained by ED confirmation of vaccination, electronic health record review, and telephone follow-up.ResultsOf the 496 participants enrolled (221 during intervention weeks and 275 during control weeks), the median (IQR) age was 39 (30-54) years, 205 (41.3%) were female, 193 (38.9%) were African American, 97 (19.6%) were Latinx, and 218 (44.0%) lacked primary care physicians. More intervention group participants, compared with control participants, stated that they would accept the vaccine in the ED (57 [25.8%] vs 33 [12.0%]; adjusted difference, 11.9 [95% CI, 4.5-19.3] percentage points; number needed to treat [NNT], 8 [95% CI, 5-22]). More intervention group participants than control participants received a COVID-19 vaccine within 30 days of their ED visit (44 [20.0%] vs 24 [8.7%]; adjusted difference, 7.9 [95% CI, 1.7-14.1] percentage points; NNT, 13 [95% CI, 7-60]). The intervention group had greater outcome effect sizes than the control group in participants who lacked a primary care physician (acceptance, 38 of 101 [37.6%] vs 16 of 117 [13.7%] [P for interaction = .004]; uptake, 31 of 101 [30.7%] vs 11 of 117 [9.4%] [P for interaction = .006]), as well as in Latinx persons (acceptance, 23 of 52 [44.2%] vs 5 of 48 [10.4%] [P for interaction = .004]; uptake, 22 of 52 [42.3%] vs 4 of 48 [8.3%] [P for interaction < .001]).Conclusions and RelevanceResults of this cluster randomized clinical trial showed that with low NNT, implementation of COVID-19 vaccine messaging platforms in EDs leads to greater vaccine acceptance and uptake in unvaccinated ED patients. Broad implementation in EDs could lead to greater COVID-19 vaccine delivery to underserved populations whose primary health care access occurs in EDs.Trial RegistrationClinicalTrials.gov Identifier: NCT05142332