Background: Nurses are responsible for ensuring safety and quality of patient care at all times. Many nursing tasks involve a degree of risk such as medication administration procedures carries the greatest risk for patients if staff nurses not follow five rights of medication administration (patient, drug, route, time and dose). Aim: the study aimed to evaluate nurses' knowledge and performance about safety measures in medication administration among staff nurses. Method: A descriptive correlational research design was utilized; the study was conducted on 350 staff nurses working at Al-Mahalla general hospital. Data was collected by using two tool, Medication Safety Measures Knowledge Assessment Questionnaire. Safe Medication Administration Observation Checklist. Results: The study results showed that total nurses' knowledge of safety measures related to medication administration was high level as well as their total performance related to medication administration. Conclusion: There was statistically significant correlation between staff nurses' knowledge and their performance of safety measures related to medication administration. Recommendation: Provision of adequate supervision and guidance for nurses. Establishing a standard of reward or promotion for nurses who follow the hospital policies related to dealing with medication administration.