Objective. The present study aimed to develop Nursing Stretch Break (NSB) application to relieve work-related musculoskeletal complications and fatigue among hospital nurses. Methods. This interventional study was conducted among 71 nurses (15 men and 56 women with a mean age of 33.32 ± 6.42) employed in Shiraz governmental hospitals, Southwest Iran, for four months. In this study, NSB was developed; it includes eight main menus for the user, including (1) Registration, (2) Stretches, (3) User panel, (4) Questions from the researcher, (5) About us, (6) Contact us, (7) Reports, and (8) Answers to questions. Data were collected pre and post-intervention via the Persian version of the Nordic Musculoskeletal Questionnaire (P-NMQ), the Persian version of the Multidimensional Assessment of Fatigue (P-MAF) Scale, the Persian version of the Numeric Rating Scale (P-NRS), and the Persian version of the Usefulness, Satisfaction, and Ease of use (P-USE) questionnaire. Results. NSB application usability testing showed that the mean scores of P-USE subscales were high. The prevalence of work-related musculoskeletal symptoms (WMSs) in the last 7 days in nurses’ body parts, except the elbows and knees, was significantly lower after the intervention than before. In addition, the intensity of work-related musculoskeletal pain/discomfort in all body parts, except the knees, was significant relief after the intervention compared to before. The results demonstrated that the difference in the mean score of the total fatigue and its subscales, except “degree of interference with activities of daily living,” was significant after the intervention compared to before. Conclusions. NSB could be a low-cost and feasible ergonomic solution to improve the nurses’ musculoskeletal health.