Background: Cancer-related fatigue is a common distressing symptom that is present in most cancer patients at some point during the disease course. According to self-regulation model, inadequate management of fatigue may lead to increased fatigue distress and worsen patients' outcomes. The aim of this study was to evaluate the effect of the application of the self-regulation model on the management of fatigue for cancer patients receiving chemotherapy. Methods: A quasi-experimental research design was used to collect data from the Clinical Oncology and Nuclear Medicine Department and its relevant outpatient's clinic of Tanta Main University Hospital. A sample of 60 patients was interviewed during their follow-up. Sociodemographic, medical data, cancer fatigue scale, and the selfregulation questionnaire were used to collect data for the study. Results: Majority were in the age group 41 to 50 and 51 to 60 years old, 50% were males, 50% females and 58% were married. Most of the patients were high school and university graduates. More than half of the patients have had the disease for more than a year and were not smoking. Majority had GIT, pancreatic, kidney and prostatic cancer. Physical, affective, and cognitive fatigue were reduced to the minimum at one month after application of the SRM with significant differences in the fatigue mean score at one month. Self-regulation was obviously improved at one month. Understanding emotions reported a significant association with affective fatigue. In addition, self-regulation and problem-solving reported a significant association with cognitive fatigue. Conclusion and recommendations: Self-regulation Model applied in this study advises that cognitive and emotional regulation influences health-related behaviours and coping behaviours which influence patients' management and control of their fatigue. Self-regulation model can be incorporated into rehabilitation programs, applied to other types of cancer and chronic illnesses and integrated into nursing curriculum and health education. Further research with a larger sample, qualitative design, and different patients' populations would add more to the nursing body of knowledge.