Background: Adolescents can benefit from engagement with health-related content on social media (e.g., viewing, commenting, or sharing content related to diseases, prevention, or healthy lifestyle). Nevertheless, such content may be distressing or exaggerated and present a challenge to mental well-being, especially during the COVID-19 pandemic. Rumination about such content may lead to COVID-19 anxiety. Yet, the individual factors that would explain the association between health-related social media use (SMU) and COVID-19 anxiety are understudied. Objective: In the current study, we aimed to fill the gap by investigating the association between health-related social media use (SMU) and COVID-19 anxiety in light of several individual factors: health anxiety, eHealth literacy, and mild and severe experience with COVID-19 infection. We (1) studied the relationship between individual factors and health-related SMU, (2) tested health anxiety as a moderator in the association between health-related SMU and COVID-19 anxiety, and (3) explored a direct effect of experience with COVID-19 on COVID-19 anxiety. Methods: Using structural equation modeling, we analyzed cross-sectional data from a representative sample of 2,500 Czech adolescents aged 11–16, 50% girls. Sociodemographic measures, health-related SMU, COVIDCOVID-19 anxiety, health anxiety, eHealth literacy, and mild and severe experience with COVID-19 infection were assessed with an anonymous online survey. The data were collected in June 2021. Results: We conducted a path analysis to test the main relationships and an additional simple-slopes analysis to explore the moderating effect of health anxiety. Higher health anxiety and eHealth literacy were associated with increased health-related SMU. The effect of experience with COVID-19 infection on both COVID-19 anxiety and health-related SMU was negligible. Health-related SMU and COVID-19 anxiety were positively associated, however, only for adolescents high in health anxiety. For other adolescents, the two variables were unrelated. Conclusion: Our findings show that adolescents with higher health anxiety and eHealth literacy engage in health-related SMU more intensively. Furthermore, for adolescents high in health anxiety, the frequency of health-related SMU is associated with the risk of COVID-19 anxiety. This is likely due to differences in media use. Adolescents with high health anxiety may use social media for content that is more likely to lead to COVID-19 anxiety compared to other adolescents. We recommend focusing on the identification of such content, which may lead to more precise recommendations regarding health-related SMU compared to cut-back on the frequency of overall SMU.