Background: Despite the beneficial effects of chemotherapy, it can also cause distressing symptoms, which can impede physical functioning, emotional state and impact on quality of life for patients with cancer. Fatigue is one of the most common and persistent symptoms of cancer, and can significantly impact a person's ability to function and participate in activities of daily living. Relaxation based interventions have been growing in recognition as supportive non-pharmacological interventions as they are relatively easy to perform, inexpensive, and can be learned by the patient for self-use. Relaxation techniques can help patients to relax physically, promote rest, enhance coping and facilitate psychological adaptation to chemotherapy. The impact of a structured relaxation-based component of a nurse-led symptom-management program on fatigue and global quality of life among patients receiving chemotherapy was investigated in the present study. Methods: A quasi-experimental pre-test–post-test control-group design was implemented, which is a quantitative approach. This study involved 200 patients receiving chemotherapy: experimental group (100 patients) and control group (100 patients). The experimental group were given the nurse-led structured symptom-management programme, which incorporated relaxation-based symptom-management strategies, and the control group were given routine institutional care. The Brief Fatigue Inventory was used to measure fatigue and the EORTC QLQ-C30 was used to measure the global quality of life. Within-group comparisons and between-group comparisons were made by comparing pre-test and post-test scores. Paired and independent statistical tests and analysis of covariance were used to assess the effect of the intervention. Results: The mean age of the experimental group was 53.07 ± 10.23 years and the control group 51.59 ± 9.51 years. In the experimental group, fatigue at the pre-test was 6.05 ± 1.50 and at the post-test was what was reported in this study, while the control group was 5.77 ± 1.40 at the pre-test and 5.60 ± 1.46 at the post-test. For between-group comparison, fatigue was statistically significant (p < 0.001) with a reported t value of 16.899 and Cohen's d of 2.390. Global quality of life increased from 57.39 ± 12.89 to 67.15 ± 13.41 in the experimental group, whereas the control group increased from 52.77 ± 12.28 to 55.88 ± 12.65. Reported between group comparison was statistically significant at p < 0.001, t = 15.434, Cohen's d = 2.183. The statistically significant ANCOVA group effects were for fatigue and global quality of life with F = 282.035 and F = 230.072, respectively, at p < 0.001. Conclusion: This study results suggest that the intervention (structured relaxation and symptom management strategies) was significantly associated with patients' chemotherapy-related fatigue and global quality of life. The results showed that relaxation-based nursing interventions have the potential to be included in supportive cancer care. Since relaxation was part of a multicomponent programme in this source study, additional RCTs are needed to assess the independent effects of relaxation therapy.