The COVID-19 pandemic has caused an overabundance of valid and invalid information to spread rapidly via traditional media as well as by internet and digital communication. Health literacy (HL) is the ability to access, understand, appraise, and apply health information, making it fundamental for finding, interpreting, and correctly using COVID-19 information. A cross-sectional study of a sample of 3500 participants representative of the Italian adult population aged 18+ years was conducted in Italy in 2021. A validated HL questionnaire was employed, including sections on coronavirus-related HL, general HL, sociodemographic characteristics, risk factors, and respondents’ lifestyle. Of our sample, 49.3% had “excellent” levels of coronavirus-related HL and 50.7% had “sufficient” (20.7%) or “limited” (30.0%) levels. Although the overall HL-COVID level was high, many participants reported difficulties dealing with COVID-19 information; in particular, participants older than 65 years, with a low education level, living in southern regions of Italy, and with high financial deprivation. Targeted public information campaigns and the promotion of HL are required for better navigation of health information environments. The COVID-19 pandemic has highlighted the need to improve HL and to prepare the general population for future emergency and non-emergency situations, confirming that HL can be considered a social vaccine