Background <p>Liver cancer remains a global public health threat, especially in Asia. Early detection through screening is crucial for improving survival rates in high-risk populations for liver cancer, however screening remains underutilized in clinical practice and inadequately addressed in China.</p> Objective <p>To explore the self-reported knowledge, attitudes, and practice patterns related to liver cancer screening among high-risk populations in China.</p> Methods <p>This cross-sectional study recruited high-risk individuals for liver cancer from multiple districts in Hunan Province, China. Of 1,600 eligible individuals invited, 1,401 completed the survey (response rate: 87.56%). Data were collected through anonymous questionnaires and analyzed from March to September 2024. The linear regression model was applied to measure the influencing factors associated with liver cancer screening practice. Associations between knowledge/attitudes and screening practices were assessed using the χ² test or the Fisher exact test.</p> Results <p>The study population (<i>N</i> = 1,401) comprised 679 (48.5%) males and 722 (51.5%) females. Only 680 participants (48.5%) reported previous liver cancer screening. Knowledge assessment revealed that 745 participants (53.2%) demonstrated fair-level knowledge, while 579 (41.3%) showed low-level knowledge. Most participants (1,077, 76.9%) exhibited positive attitudes toward screening, scoring above 50 points. Statistical analysis revealed a significant association between attitudes and screening practices (<i>P</i> &lt; 0.001), while knowledge levels showed no correlation with screening practices (<i>P</i> = 0.696).</p> Conclusions <p>This study reveals significant knowledge deficits regarding liver cancer screening among high-risk populations in China, which correlates with their attitudes and screening practices. These findings emphasize the need for targeted educational programs to enhance knowledge and improve screening participation among high-risk populations.</p>