Background: During the COVID-19 pandemic, poor hand hygiene compliance was observed among nurses, in spite of the fact that keeping hands clean is a simple, affordable method that reduces the risk of spreading health care-associated infections. The aim of the study was to investigate the determinants of nurses' non-compliance with hand hygiene practices during the COVID-19 pandemic. A descriptive exploratory design was utilized to fulfil the aim of the study. A convenient sample of all adult nurses who worked in the four randomly selected medical and surgical wards at a big teaching hospital affiliated with Cairo University Hospitals, Egypt. The following tools were utilized to collect study data: (a) Demographic and Background Information Form; (b) Hand Hygiene Practice Direct Observation Form; and (c) Determinants of Nurses' Non-Compliance with Hand Hygiene Practices Questionnaire. Results: As regards non-compliance rates, 69.2% of the study sample were not performing the opportunities, which were the five moments of hand hygiene. while 30.8 percent of them had performance concerns. In relation to the determinants of non-compliance with hand hygiene practices; 46.2% of the study sample complained of having a heavy workload and a lack of time; 41.5% of them had to take prompt actions and many procedures they had to do; and 40% of the study sample preferred to meet patients' needs rather than wash their hands. Conclusion: Regarding the studied nurses' non-compliance, more than two thirds of them were not performing the opportunities which were the five moments of hand hygiene. The most significant determinants of nurses' non-compliance with hand hygiene practices were their workload, lack of time, prompt actions, and many procedures they had to do. Recommendations: With the intention of turning knowledge into action, shifting attitudes into constructive behavior, and promoting proper hand washing procedures, ongoing monitoring and evaluation should be implemented.