Background: Treatment with tissue plasminogen activator (TPA) for acute stroke requires intensive care of the patient. The risk of thrombolytic therapy and the need for rapid interventions make it clear that the nursing role during this time is crucial. The aim: This study aims to assess the nurses' Performance regarding monitoring of patients with stroke during administration of Tissue Plasminogen Activator drug. Study design: A descriptive exploratory design. Subject: A convenient sample of all nurses (30) working at the previously mentioned setting were recruited to participate in the study. Setting: This study was conducted at the stroke unit at the neurology department affiliated to Ain Shams University Hospital. Tools: two tools were used for data collection; self-administered questionnaire and nurses’ practice observational checklist. Results and conclusion: the results of this study showed that, all of the studied nurses had unsatisfactory total knowledge and total practice and two thirds of the studied nurses had negative attitude regarding monitoring patients with ischemic stroke during administration of TPA drug. A positive statistically significant correlation between total level of nurses` practice and their total level of knowledge was found and there was no statistically significant correlation between total level of nurses` practice and knowledge and their total level of attitude. Recommendation: Providing in-service educational programs and upgrading courses based on evidence-based guidelines based on nurses' needs to improve their knowledge and practice related to administration of TPA drug. Knowledge sources in Arabic language must be provided for nurses in work place such as simplified and comprehensive educational guidelines, policies, booklets and websites about TPA administration and the role of nurse pre, during and after administration.