Background: Peripheral intravenous cannula (PIVC) are a frequent nursing technique used for the infusion of beverages, medicines, and blood products and are required by the majority of patients. As a result, it is critical to maintain a sufficient supply of PIVC because they are prone to problems such as obstruction, phlebitis, and exudation, necessitating frequent replacement. However, post-insertion PIVC failure is common, most likely due to inconsistencies in maintenance practices such as flushing. As a result, hospital policies contribute to a lack of practice and awareness about this issue, which improves clinical education for nurses and patient care. Aim: This study aimed to assess nurses' practice and knowledge of peripheral intravenous cannula flushing pre-therapy administration at medical-surgical wards. Subjects and Methods: A descriptive research design was utilized. A purposive sample of sixty-two nurses who were working in the medical-surgical wards at Teaching Hospital, Ismailia city, was used. Two tools were used for data collection: a self-administered questionnaire to identify nurses' personal data and knowledge and an observational checklist to assess nurses' practice. Results: The findings of this study revealed that most of the studied nurses had a fair level of knowledge and an unsatisfactory level of practice with regard to peripheral intravenous cannula flushing. Furthermore, there was a statistically significant positive correlation between their total knowledge and practice scores, with a p value≤0.05. Conclusion: In the present study, the nurses' level of practice was inadequate, and their knowledge of peripheral intravenous cannula flushing was fair. Additionally, there was a highly statistically significant relationship between total performance score (practices and knowledge) and their qualifications, with a p value≤0.05. Recommendations: Nurses should have access to ongoing educational opportunities and in-service training programs on short peripheral catheter intravenous flushing to improve their expertise.