Background As the COVID-19 pandemic continues to affect life in the United States, the important role of nonpharmaceutical preventive behaviors (such as wearing a face mask) in reducing the risk of infection has become clear. During the pandemic, researchers have observed the rapid proliferation of misinformed or inconsistent narratives about COVID-19. There is growing evidence that such misinformed narratives are associated with various forms of undesirable behavior (eg, burning down cell towers). Furthermore, individuals’ adherence to recommended COVID-19 preventive guidelines has been inconsistent, and such mandates have engendered opposition and controversy. Recent research suggests the possibility that trust in science and scientists may be an important thread to weave throughout these seemingly disparate components of the modern public health landscape. Thus, this paper describes the protocol for a randomized trial of a brief, digital intervention designed to increase trust in science. Objective The objective of this study is to examine whether exposure to a curated infographic can increase trust in science, reduce the believability of misinformed narratives, and increase the likelihood to engage in preventive behaviors. Methods This is a randomized, placebo-controlled, superiority trial comprising 2 parallel groups. A sample of 1000 adults aged ≥18 years who are representative of the population of the United States by gender, race and ethnicity, and age will be randomly assigned (via a 1:1 allocation) to an intervention or a placebo-control arm. The intervention will be a digital infographic with content based on principles of trust in science, developed by a health communications expert. The intervention will then be both pretested and pilot-tested to determine its viability. Study outcomes will include trust in science, a COVID-19 narrative belief latent profile membership, and the likelihood to engage in preventive behaviors, which will be controlled by 8 theoretically selected covariates. Results This study was funded in August 2020, approved by the Indiana University Institutional Review Board on September 15, 2020, and prospectively registered with ClinicalTrials.gov. Conclusions COVID-19 misinformation prophylaxis is crucial. This proposed experiment investigates the impact of a brief yet actionable intervention that can be easily disseminated to increase individuals’ trust in science, with the intention of affecting misinformation believability and, consequently, preventive behavioral intentions. Trial Registration ClinicalTrials.gov NCT04557241; https://clinicaltrials.gov/ct2/show/NCT04557241 International Registered Report Identifier (IRRID) PRR1-10.2196/24383