Background Fatigue is one of the more frequent symptoms of multiple sclerosis and could adversely effect on patients general health status. Aim: Evaluate the effect of nursing intervention on fatigue for multiple sclerosis patients. Design A quasi-experimental design was utilized. Setting The study was carried out in the neurological department) at El Demerdash hospital. Subjects A convenience sample of available patients within 6 months of about 144 patients involved. Tools Three tools were used for data collection; first tool: patients' socio-demographic and health status characteristics; knowledge questionnaire and patient-reported fatigue self-care practices questionnaire second tool: Fatigue Severity Scale. 3rd tool: Modified Fatigue Impact Scale. Results: The multiple sclerosis patients' means ± SD scores in all knowledge items were improved after fatigue nursing intervention. Also, a highly statistically significant improvement in all items of reported pre and post fatigue intervention practices (p-value < 0.001). There was a statistically significant strong direct correlation between total scores of pre and post knowledge and reported self-care practices of fatigue nursing interventions (p> 0.001). Significant improvement in the reported multiple sclerosis patients' fatigue severity scores means level in the post-test than that of the pre-test, P < 0.001. Conclusion Implementation of nursing intervention could improve fatigue and decrease its severitywithimproved the patients' knowledge and fatigue nursing intervention reported practices. Also, there was noticed statistically significant strong positive correlation between total scores of pre-and post-knowledge and with total scores of pre- and post-reported practices of fatigue nursing intervention. Recommendations Implementation of fatigue nursing intervention for every patient with Multiple sclerosis to equip them with the knowledge essential to undertake fatigue intervention and achieve long-lasting control of fatigue. Conducting health educational programs and campaigns to raise the multiple sclerosis patients' awareness about the disease and fatigue intervention practices.