Background: Although delirium during critical illness is a common health problem with a high prevalence rate in mechanically ventilated patients, it is always under-recognized and undertreated by critical care nurses. Studies have proven that delirium is associated with short and long-term disabilities, complicating the course of critical illness and impairing post-discharge quality of life. Since delirium prevention is better than cure, it is imperative to adopt the ABCDEF bundle and incorporate it as part of routine care within the Intensive Care Unit (ICU) to prevent and treat delirium in critically ill patients. Objective: To investigate the effect of implementing a delirium prevention bundle on the clinical outcomes of critically ill patients. Settings: This study was conducted in five general ICUs at Alexandria Main University Hospital, namely: unit I, unit II, unit III, Unit IV, and El-Mowasaat general ICU. Subjects: A convenience sample of at least 100 critically ill patients was randomly assigned into 50 control groups and 50 intervention groups). Tools: Three tools were used to conduct this study including the Confusion Assessment Method for the ICU-7 (CAM-ICU-7) Delirium Severity Scale, Mini-Mental State Examination (MMSE), and Assessment of Clinical Outcomes. Results: The percentage of delirium occurrence in the control group was twice as high as in the intervention group with the most severe and durable form noted in the control group. Moreover, a statistically significant difference was found between the intervention and control groups regarding the level of cognitive impairment and clinical outcomes. In other words, impaired cognition, prolonged mechanical ventilation, longer length of stay, constant use of physical restraints and anti-delirious drugs, and occurrence of adverse events were noticed more in the control group, unlike the intervention group. Conclusion: ABCDEF bundle use in critically ill patients was found significantly effective in mitigating the effect of delirium and improving patients' clinical outcomes. Recommendations: More attention should be directed toward delirium management by critical care nurses to prevent occurrence and avoid related complications. Adoption of systems of care that incorporate the ABCDEF bundle as part of routine care should be emphasized. Teaching and training about delirium significance and presentation as well as the importance of the ABCDEF bundle should be taught to nursing students as well.