Background: Through the coronavirus (COVID-19) pandemic, front-line nurses meet immense mental health challenges. It is actually a global health threat attributed to a negative impact on the mental health and well-being of the people. Aim: To study the effectiveness of psycho-educational program to alleviate depression, anxiety, stress, pessimism and provide optimism for COVID-19 isolation nurses. Design: A quasi-experimental two-group (randomized control trial) was utilized in this study. Participants: A purposive sample of sixty nurses were involved in this study. Tools: A constructed interview schedule was utilized to collect data; Depression, Anxiety and Stress Scale-21; and Optimism and Pessimism Scale. The training program consisted of 14 sessions. Results: Revealed that there were highly statistically significant relations between depression, anxiety, stress, and pessimism pre/post program in “experimental group". Also, there were statistically significant relations between pessimism and anxiety among the control group pre/post observations. Conclusion: The program had a great positive effect on nurses who were caring for patients infected with coronavirus in reduced “levels of stress, anxiety, depression, pessimism and increased level of optimism". Recommendations: The nursing staff must be prepared to challenge any pandemic in the future to alleviate their levels of depression, anxiety, stress pessimism, and provide optimism and feelings of hope.