Abstract Background and Objectives This study aimed to explore the association between cyberchondria and eHealth literacy in the general Chinese population, and to assess how this relationship changes between urban and rural residents. Methods Data obtained from a web-based, cross-sectional survey that evaluate cyberchondria and its impact on health in February 2024. The Cyberchondria Severity Scale - 12 item was used to measure the cyberchondria, while the eHealth Literacy Scale was used to evaluate eHealth literacy. Descriptive analysis was used to describe the background characteristics of the participants. Then, a multivariable linear regression model was then performed for urban and rural subsample to examine the relationship between cyberchondria and eHealth literacy, respectively, providing a comparative analysis between the urban and rural populations. Results A total of 634 individuals completed the questionnaire. The average age was 33.2 years (SD = 7.4), with approximately 50.3% (n = 319) being female. Urban residents made up 71.4% (n = 451) of the participants. The mean eHEALS scores for urban and rural residents were 31.9 (SD = 4.3) and 30.4 (SD = 4.2), respectively. The CSS-12 scores for urban residents were 40.3 (SD = 7.58) and for rural residents were 39.1 (SD = 7.2). Linear regression analyses showed a significant association between eHealth literacy and cyberchondria for urban residents (Beta = 0.30, p < 0.001), but age and education level had no significant impact. For rural residents, a statistically significant association between eHealth literacy and cyberchondria was also observed (Beta = 0.40, p = 0.002). Conclusions Overall, eHealth literacy consistently predicts cyberchondria severity in both urban and rural samples. Higher eHealth literacy is linked to greater cyberchondria, especially in rural areas. Future research should explore other potential mediators, including psychological factors, internet usage patterns, and access to healthcare services. Key messages • eHealth literacy strongly predicts cyberchondria severity in both urban and rural populations, with a notably stronger impact observed in rural settings. • Urban and rural differences highlight the need for customized digital health literacy programs to effectively address region-specific challenges and behaviors.