Background: Nurses' competencies related to high alert medications include their knowledge of these drugs, its indications, contraindications, side effects and interactions with other drugs. Nurses have to be able to accurately calculate dosages and administer medication using the correct route and technique. Aim of the: This study was carried out to assess nurses' competence level toward high-alert medications before and after application of the designed nursing protocol. Design: One group quasi-experimental research utilized to fulfill the aim of this study. Sample: All critical care nurses on duty regardless of their personal data were included (n=67 nurses). Settings: present study was conducted in five critical care units including (trauma ICU, coronary care unit, medical intensive care unit, urology ICU and nephrology ICU) at Minia university hospitals. Tools of data collection: Data was collected through utilization of two tools. First:  Demographic data sheet of nurses. Second: Competence level evaluation tool. The second tool was consisting of three parts: first part was knowledge assessment domain, second part was observational checklist (practice domain) and third part was attitude assessment domain. Results:  The studied nurses had significant differences in knowledge, practice and attitude levels toward HAMs at pre and post the application of a designed nursing protocol. Conclusion: Based on the results of this study, the designed nursing protocol about HAMs improved nurses' knowledge, practice and attitude toward HAMs. Recommendations: Greater attention and frequently evaluation of nurses' competence level toward HAMs should be maintained by continuous in service training and replication of this study should be done on a larger sample in different CCUs.