Background: Mastectomy causes negative impact on patients’ quality of life (QOL), thus highlight critical clues for improving QOL through enhancement self-management for these patients are needed. The aim of the study was to determine the effect of self-management guidelines on the QOL for post-mastectomy patients. Method: This quasi-experimental study was conducted in Oncology Department, Suez Canal University Hospital, Ismailia, Egypt. A purposive sample of 72 patients with post-mastectomy was included. Study tools (1) Interviewing questionnaire comprised of three parts was used; first part included socio demographic characteristics, second part included medical data, third part included patients’ knowledge questionnaire (2) self-management scale. (3) QOL scale included Short-Form 36 (SF-36) Health Survey. Three tools were used pre- and post-implementation of the self-management guidelines. Results: The patients’ knowledge scores and self- management scales were both significantly improved after implementation of guidelines. SF-36 QOL score was extremely better after implementation of guidelines (28.7±7.7 versus 80.0±6.4, respectively). There was a significant positive correlation between self- management and QOL post-guidelines implementation (p < 0.0001). Conclusions: There was a significant improvement in post-mastectomy patients QOL after self-management guidelines implementation. There was a significant positive correlation between self- management and QOL post-guidelines implementation for post-mastectomy patients. Recommendations: Self-management guidelines should be conducted for post-mastectomy patients as they are the key to improving their QOL.