BackgroundSince its outbreak in January 2020, COVID-19 has quickly spread worldwide and has become a global pandemic. Social media platforms have been recognized as important tools for health-promoting practices in public health, and the use of social media is widespread among the public. However, little is known about the effects of social media use on health promotion during a pandemic such as COVID-19. ObjectiveIn this study, we aimed to explore the predictive role of social media use on public preventive behaviors in China during the COVID-19 pandemic and how disease knowledge and eHealth literacy moderated the relationship between social media use and preventive behaviors. MethodsA national web-based cross-sectional survey was conducted by a proportionate probability sampling among 802 Chinese internet users (“netizens”) in February 2020. Descriptive statistics, Pearson correlations, and hierarchical multiple regressions were employed to examine and explore the relationships among all the variables. ResultsAlmost half the 802 study participants were male (416, 51.9%), and the average age of the participants was 32.65 years. Most of the 802 participants had high education levels (624, 77.7%), had high income >¥5000 (US $736.29) (525, 65.3%), were married (496, 61.8%), and were in good health (486, 60.6%). The average time of social media use was approximately 2 to 3 hours per day (mean 2.34 hours, SD 1.11), and the most frequently used media types were public social media (mean score 4.49/5, SD 0.78) and aggregated social media (mean score 4.07/5, SD 1.07). Social media use frequency (β=.20, P