Background: Post mastectomy lymphedema is a chronic disease that negatively affects physical, social, psychological and emotional well-being. So patient education regarding lymphedema is crucial to enhance knowledge and quality of life of post mastectomy women. Study Aim: To evaluate effect of educational nursing program on knowledge and quality of life of women with post mastectomy lymphedema. Research design: A quasi experimental design with a pre–posttest approach was utilized. Subjects: A convenient sample of forty women with post-mastectomy lymphedema participated in this study. Setting: The study was conducted in the breast, oncology outpatient clinics and Rheumatology and rehabilitation unit at Assiut University Hospital. Tools: Tool (I) Women's Structured Interview Questionnaire, including three sections: Women's demographic data, Women's medical history and Pre/Post Knowledge Assessment Questionnaire. Tool (II): Lymphedema Quality of Life Questionnaire-Arm. Results: The mean age of the women was 47.67±6.45 years, regarding women's total knowledge, 92.5% had unsatisfactory scores before the program. In contrast, 85.0% and 65.0% achieved satisfactory scores immediately and three months after program implementation, respectively. Moreover, total quality of life means score was improved post implementation of program (77.98±7.31versus 47.75±9.934, respectively; p < 0.001**), with higher scores indicating worse quality of life according to Lymphedema Quality of Life Questionnaire-Arm. Conclusion: Implementing educational nursing program significantly enhanced knowledge and quality of life in women with post-mastectomy lymphedema. Recommendation: Create a multidisciplinary lymphedema outpatient clinic staffed by a physician, physiotherapist, social worker, and lymphedema specialist nurse to provide integrated care through diagnosis, treatment, education, and ongoing follow-up.