To examine knowledge, attitude, and practice regarding postoperative delirium and the relationships among cardiac surgery nurses in China.Postoperative delirium is a prevalent and devastating complication following cardiac surgery. Nurses play a part in multi-disciplinary collaboration for preventing and managing postoperative delirium, of whom knowledge, attitude, and practice are essential.A cross-sectional multi-centre study.Nurses from cardiac surgery wards and intensive care units of five tertiary hospitals in Wuhan, Hubei Province, China were enrolled. Data were gathered online using a self-administered questionnaire. Student's t-test, or analysis of variance, or non-parametric tests were performed to compare differences across groups. Bootstrapping mediation analysis was conducted to examine the relationship between knowledge, attitude, and practice. The STROBE checklist was used for the reporting of this study.Of 429 nurses, a moderate level of knowledge and high levels of attitude and practice regarding postoperative delirium were revealed. Nurses with higher education, higher academic title, 5-10 years of practice in nursing and cardiac surgery nursing exhibited increased knowledge. With advanced age, practice in a specialised hospital, and training experience, nurses reported a better degree of practice. Attitude played a full mediating effect in the relationship between knowledge and practice, accounting for 81.82% of the total effects.Knowledge, attitude, and practice regarding postoperative delirium are promising among Chinese cardiac surgery nurses, with knowledge of screening tools and perioperative nonpharmacological interventions and practice of screening in need of enhancement. Attitudes act as an intermediary between knowledge and practice regarding postoperative delirium.Innovative and stratified in-service education is warranted to address knowledge enhancement. Meanwhile, organisations are suggested to make efforts to foster nurses' positive attitudes, particularly in creating a favourable culture and developing institutional protocols for postoperative delirium management to improve practice.This study is focused on cardiac surgery nurses' knowledge, attitude, and practice regarding postoperative delirium, and the research questions and design are from clinical nursing practice, literature review, and expert panel review, in which the patient or public is temporarily not involved.© 2023 John Wiley & Sons Ltd.