Background Innovative approaches to the dissemination of evidence-based COVID-19 health messages are urgently needed to counter social media misinformation about the pandemic. To this end, we designed a short, wordless, animated global health communication video (the CoVideo), which was rapidly distributed through social media channels to an international audience. Objective The objectives of this study were to (1) establish the CoVideo’s effectiveness in improving COVID-19 prevention knowledge, and (2) establish the CoVideo’s effectiveness in increasing behavioral intent toward COVID-19 prevention. Methods In May and June 2020, we enrolled 15,163 online participants from the United States, Mexico, the United Kingdom, Germany, and Spain. We randomized participants to (1) the CoVideo arm, (2) an attention placebo control (APC) arm, and (3) a do-nothing arm, and presented 18 knowledge questions about preventive COVID-19 behaviors, which was our first primary endpoint. To measure behavioral intent, our second primary endpoint, we randomized participants in each arm to five list experiments. Results Globally, the video intervention was viewed 1.2 million times within the first 10 days of its release and more than 15 million times within the first 4 months. Knowledge in the CoVideo arm was significantly higher (mean 16.95, 95% CI 16.91-16.99) than in the do-nothing (mean 16.86, 95% CI 16.83-16.90; P<.001) arm. We observed high baseline levels of behavioral intent to perform many of the preventive behaviors featured in the video intervention. We were only able to detect a statistically significant impact of the CoVideo on one of the five preventive behaviors. Conclusions Despite high baseline levels, the intervention was effective at boosting knowledge of COVID-19 prevention. We were only able to capture a measurable change in behavioral intent toward one of the five COVID-19 preventive behaviors examined in this study. The global reach of this health communication intervention and the high voluntary engagement of trial participants highlight several innovative features that could inform the design and dissemination of public health messages. Short, wordless, animated videos, distributed by health authorities via social media, may be an effective pathway for rapid global health communication during health crises. Trial Registration German Clinical Trials Register DRKS00021582; https://tinyurl.com/6r4zkbbn International Registered Report Identifier (IRRID) RR2-10.1186/s13063-020-04942-7