In the fight against the unique and potentially lethal Coronavirus 2019 (COVID-19) pandemic, nurses are at the forefront of the medical community. Inadequate information and inappropriate attitudes among nurses can directly impact behaviors, resulting in poor infection control and disease spread. Aim of the research: This research aimed to compare the knowledge, attitude, and practice toward COVID-19 and the observed difficulties toward infection control between nurses in Family Health Center sand hospitals. Setting: The research was managed at Family Health Center, El-Me University Hospital, and El-Shatby University Hospital for Maternity and Child in Alexandria. Multistage sample: was used to choose the Family Health Center, 400 nurses agreed to contribute to the research from the above-selected settings. Subjects and Methods: A cross-sectional comparative research design technique was used in this research. Nurses „knowledge, attitude, and practice about COVID-19 disease were evaluated using a self-administered validated questionnaire. Results: The studied subjects in both groups (44%, 56% respectively) explained that social media was the main source of information regarding COVID-19. Majority of the studied subjects in Family Health Center had poor knowledge, practice, and attitude (66%, 58%, 52% respectively) while most of the studied subjects in hospitals had good knowledge, practice and attitude regarding COVID-19 (100%, 86%, 90% respectively), with highly statistically significant differences between the two groups (P <0.001). The studied subjects in both groups perceived a number of barriers (68%, 16% respectively) to infection control practice toward COVID-19. Conclusion: Hospital nurses have better knowledge, practice, and attitude regarding COVID-19 related to those of Family Health Centers. Recommendation: Institute a comprehensive training program targeting Family Health Center nurses to enhance precautionary and preventive measures concerning COVID-19. Keywords: Knowledge, Attitude, Practice, Perceived Barriers, Family Health Center, Hospital Nurses, COVID-19 & Nurses.