The corona virus undergoes spontaneous mutations over time and generates new variants and strains,  posing significant challenges to health care systems across the globe. Aim was to assess challenges facing nurses during and beyond new mutations of COVID-19 pandemic in relation to perceived health facility preparedness and organizational support. Method: Design: A descriptive correlational design. Setting: The study was conduct at all over Shibin El-Kom centers and two affiliated villages, Menoufia Governorate, Egypt. Sample: Convenience sampling technique was utilized to recruit 275 nurses. Instruments: 1. Questionnaire about challenges facing nurses, 2. Survey of perceived organizational support, and 3. Survey of perceived of health facility's preparedness. Result: The highest nurses’ percentage reported being faced with increased level of current challenges while this level decreased regarding future challenges. Moderate perception of organizational support and the institution preparedness was reported by the highest percentage of them. A highly significant negative correlation was reported between future challenges faced by nurses and their perception of organizational support. There was a highly significant relationship between total nurses' perception of health facility's preparedness and their total perception of organizational support. Conclusions: New mutations of COVID-19 pandemic are creating new challenges on nurses currently and at future. Nurses' perception of organizational support and facility preparedness minimizes their perception of being challenged during and beyond new mutations of COVID-19 pandemic. Recommendation: nurse managers aid in gaining a greater knowledge of nurses, allowing them to implement effective actions to address the formidable problems facing nurses confront during current and future public health emergencies.                                                                                                                                                

 Challenges, COVID19, Organizational support, Perception, Preparedness.                       Keywords: