Health literacy is the ability of individuals to access, process, and understand health information to make decisions regarding treatment and their health on the whole / it is critical to maintain and improve public health. However, the health literacy of urban and rural populations in China has been little known. Thus, this study aims to assess the status of health literacy and explore the differences of its possible determinants (e.g., socio-economic factors) among urban and rural populations in Henan, China. A cross-sectional study, 78,646 participants were recruited from a populous province in central China with a multi-stage random sampling design. The Chinese Resident Health Literacy Scale was adopted to measure the health literacy of the respondents. In the participants, the level of health literacy (10.21%) in central China was significantly lower than the national average, and a big gap was identified between urban and rural populations (16.92% vs. 8.09%). A noticeable difference was reported in different aspects and health issues of health literacy between urban and rural populations. The health literacy level was lower in those with lower levels of education, and a significant difference was identified in the level of health literacy among people of different ages and occupations in both urban and rural areas. Note that in rural areas, as long as residents educated, they all had higher odds to exhibit basic health literacy than those uneducated / in rural areas, compared with those aged 15 to 24 years, residents aged 45 to 54 years (OR = 0.846,95% CI (0.730, 0.981)), 55 to 64 years (OR = 0.716,95% CI (0.614, 0.836)) and above 65 years (OR = 0.679, 95% CI (0.567, 0.812)) were 84.6%, 71.6%, and 67.9%, respectively, less likely to exhibit basic health literacy. Considering the lower health literacy among rural residents compared with their urban counterparts, a reorientation of the health policy-making for Chinese rural areas is recommended. This study suggests that urban&ndash / rural disparity about health literacy risk factors should be considered when implementing health literacy promotion intervention.