Background Adherence to nonpharmaceutical interventions for COVID-19, including physical distancing, masking, staying home while sick, and avoiding crowded indoor spaces, remains critical for limiting the spread of COVID-19. Objective The aim of this study was to test the effectiveness of using various persuasive appeals (deontological moral frame, empathy, identifiable victim, goal proximity, and reciprocity) at improving intentions to adhere to prevention behaviors. Methods A randomized online experiment using a representative sample of adult Canadian residents with respect to age, ethnicity, and province of residence was performed from March 3 to March 6, 2021. Participants indicated their intentions to follow public health guidelines, saw one of six flyers featuring a persuasive appeal or no appeal, and then rated their intentions a second time. Known correlates of attitudes toward public health measures were also measured. Results Intentions to adhere to public health measures increased in all appeal conditions. The message featuring an empathy appeal resulted in a greater increase in intentions than the control (no appeal) message. Moreover, the effectiveness of persuasive appeals was moderated by baseline intentions. Deontological, empathy, identifiable victim, and reciprocity appeals improved intentions more than the control message, but only for people with lower baseline intentions to adhere to nonpharmaceutical interventions. Conclusions Public health marketing campaigns aiming to increase adherence to COVID-19 protective behaviors could achieve modest gains by employing a range of persuasive appeals. However, to maximize impact, it is important that these campaigns be targeted to the right individuals. Trial Registration ClinicalTrials.gov NCT05722106; https://clinicaltrials.gov/ct2/show/NCT05722106