A well-established treatment for acute myocardial infarction, thrombolytic therapy has time-dependent advantages. When patients are admitted to the hospital with a suspected myocardial infarction, nurses are frequently the first medical personnel to evaluate them. There are various procedures for prompt evaluation and treatment. Aim: to determine the effect of educational guidelines implementation on nurses' performance regarding thrombolytic therapy management among patients with acute myocardial infarction. Subject and Methods: Quasi-Experimental research design was utilized to achieve the aim of the study. A sample of convenience of 50 nurses working in the coronary care unit. Data was collected at a coronary care unit affiliated with Sohag University Hospital. Three tools were utilized; included: (I) Personal data, (II) a Thrombolytic knowledge questionnaire, and (III) a Thrombolytic management observational checklist. Results: There was a statistically significant improvement in the nurses' knowledge and practice mean scores regarding thrombolytic therapy management post-educational guidelines implementation compared to pre-educational guidelines implementation. A highly statistically significant correlation was found between the overall performance before and after a month of implementing educational guidelines. Conclusion: Educational guidelines implementation has a positive effect on improving nurses' performance regarding thrombolytic therapy management among patients with acute myocardial infarction. Recommendations: The study suggested providing upgrading courses equipped with evidence-based recommendations based on nurses' need to enhance their performance in administering thrombolytic therapy. Furthermore, it is advised to monitor nurses' practices regarding the delivery of thrombolytic therapy.