<p>Misperceptions about nicotine are associated with reduced smoking cessation success and a lower likelihood of using less harmful nicotine products. Three priority populations – Black/African American adults, rural adults, and young adults who smoke in the United States – tend to hold more nicotine false beliefs relative to other groups and are at risk for poor smoking cessation outcomes. The present study used an optimization phase in the form of a 2³ factorial design to identify the curiosity-eliciting message components (social signals, questions, ratings) with the greatest likelihood of reducing nicotine false beliefs in each priority population (<i>n</i> = 200 for each population). Following message optimization, we compared exposure to targeted messages (from the optimization phase) with no message exposure and exposure to standard nicotine messages in new samples (<i>n</i> = 200 for each priority population). Targeted messages significantly reduced nicotine false beliefs (and other relevant outcomes) in Black/African American adults who smoke and rural adults who smoke. In young adults who smoke, targeted messages significantly reduced nicotine false beliefs compared to the no message exposure condition, but did not show additional benefits beyond standard nicotine messages. Findings highlight the benefit of an optimization phase and curiosity-eliciting strategies in messages designed to reduce nicotine false beliefs.</p>