During the Coronavirus Disease 2019 (COVID-19) epidemic, many health professionals used social media to promote preventative health behaviors. We conducted a randomized controlled trial of the effect of a Facebook advertising campaign consisting of short videos recorded by doctors and nurses to encourage users to stay at home for the Thanksgiving and Christmas holidays (NCT04644328 and AEARCTR-0006821). We randomly assigned counties to high intensity (n = 410 (386) at Thanksgiving (Christmas)) or low intensity (n = 410 (381)). The intervention was delivered to a large fraction of Facebook subscribers in 75% and 25% of randomly assigned zip codes in high- and low-intensity counties, respectively. In total, 6,998 (6,716) zip codes were included, and 11,954,109 (23,302,290) users were reached at Thanksgiving (Christmas). The first two primary outcomes were holiday travel and fraction leaving home, both measured using mobile phone location data of Facebook users. Average distance traveled in high-intensity counties decreased by −0.993 percentage points (95% confidence interval (CI): –1.616, −0.371; P = 0.002) for the 3 days before each holiday compared to low-intensity counties. The fraction of people who left home on the holiday was not significantly affected (adjusted difference: 0.030; 95% CI: −0.361, 0.420; P = 0.881). The third primary outcome was COVID-19 infections recorded at the zip code level in the 2-week period starting 5 days after the holiday. Infections declined by 3.5% (adjusted 95% CI: −6.2%, −0.7%; P = 0.013) in intervention compared to control zip codes. Social media messages recorded by health professionals before the winter holidays in the United States led to a significant reduction in holiday travel and subsequent COVID-19 infections.