Social distancing is critical to the control of COVID-19, which has disproportionately affected the Black community. Physician-delivered messages may increase adherence to these behaviors. To determine whether messages delivered by physicians improve COVID-19 knowledge and preventive behaviors and to assess the differential effectiveness of messages tailored to the Black community. This randomized clinical trial of self-identified White and Black adults with less than a college education was conducted from August 7 to September 6, 2020. Of 44 743 volunteers screened, 30 174 were eligible, 5534 did not consent or failed attention checks, and 4163 left the survey before randomization. The final sample had 20 460 individuals (participation rate, 68%). Participants were randomly assigned to receive video messages on COVID-19 or other health topics. Participants saw video messages delivered either by a Black or a White study physician. In the control groups, participants saw 3 placebo videos with generic health topics. In the treatment group, they saw 3 videos on COVID-19, recorded by several physicians of varied age, gender, and race. Video 1 discussed common symptoms. Video 2 highlighted case numbers; in one group, the unequal burden of the disease by race was discussed. Video 3 described US Centers for Disease Control and Prevention social distancing guidelines. Participants in both the control and intervention groups were also randomly assigned to see 1 of 2 American Medical Association statements, one on structural racism and the other on drug price transparency. Knowledge, beliefs, and practices related to COVID-19, demand for information, willingness to pay for masks, and self-reported behavior. Overall, 18 223 participants (9168 Black; 9055 White) completed the survey (9980 [55.9%] women, mean [SD] age, 40.2 [17.8] years). Overall, 6303 Black participants (34.6%) and 7842 White participants (43.0%) were assigned to the intervention group, and 1576 Black participants (8.6%) and 1968 White participants (10.8%) were assigned to the control group. Compared with the control group, the intervention group had smaller gaps in COVID-19 knowledge (incidence rate ratio [IRR], 0.89 [95% CI, 0.87-0.91]) and greater demand for COVID-19 information (IRR, 1.05 [95% CI, 1.01-1.11]), willingness to pay for a mask (difference, $0.50 [95% CI, $0.15-$0.85]). Self-reported safety behavior improved, although the difference was not statistically significant (IRR, 0.96 [95% CI, 0.92-1.01]; P = .08). Effects did not differ by race (F = 0.0112; P > .99) or in different intervention groups (F = 0.324; P > .99). In this study, a physician messaging campaign was effective in increasing COVID-19 knowledge, information-seeking, and self-reported protective behaviors among diverse groups. Studies implemented at scale are needed to confirm clinical importance. ClinicalTrials.gov Identifier: NCT04502056.