Adherence to the delirium bundle intervention is sub-optimal in routine practice, and inappropriate use of the instructional design of interventions may result in higher cognitive load among nurses. It remains unclear whether the Clinical Decision Support System (CDSS) Assisted Prevention and Management for Delirium (CDSS-AntiDelirium) results in the improvement of adherence to delirium intervention and the reduction of extraneous cognitive load, as well as improving adherence to delirium intervention, among nurses in the intensive care unit (ICU).This study (named the CDSSD-ICU) is a multicentre, prospective, cluster randomized controlled clinical trial. A total of six ICUs in two hospitals will be randomized in a 1:1 ratio to receive either the CDSS-AntiDelirium group or the delirium guidelines group. The CDSS-AntiDelirium consists of four modules: delirium assessment tools, risk factor assessment, a nursing care plan, and a nursing checklist module. Each day, nurses will assess ICU patients with the assistance of the CDSS-AntiDelirium. A total of 78 ICU nurses are needed to ensure statistical power. Outcome assessments will be conducted by investigators who are blinded to group assignments. The primary endpoint will be adherence to delirium intervention, the secondary endpoint will be nurses' cognitive load measured using an instrument to assess different types of cognitive load. Repeated measures analysis of variance will be used to detect group differences. A structural equation model will be used to clarify the mechanism of improvement in adherence.Although the CDSS has been widely used in hospitals for disease assessment, management, and recording, the applications thereof in the area of delirium are still in infancy. This study could provide scientific evidence regarding the impact of a CDSS on nurses' adherence and cognitive load and promote its further development in future studies.ChiCTR1900023711 (Chinese Clinical Trial Registry).Copyright: © 2023 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.