Background: While chemotherapy is a key element of the treatment process, it is often associated with treatment-related symptoms that have a negative impact on physical functioning, emotional state, nutrition intake, daily functioning, treatment experience, and overall quality of life. Common side effects of chemotherapy include fatigue and nausea. While pharmacology is a vital aspect of supportive oncology care, structured nursing interventions to assess symptoms, educate patients, provide nutritional support, help conserve energy, promote relaxation, and teach self-management and follow-up can also support patients during chemotherapy. The effectiveness of a nurse-led symptom management programme on the symptom of fatigue, nausea and global quality of life for patients receiving chemotherapy was evaluated in the present study. Methods: The quasi-experimental design in the form of quantitative pre-test – post test control group design was used. This study was conducted on 200 adult patients receiving chemotherapy, 100 patients were given into the experimental group, 100 patients were given into the control group. The structured nurse-led symptom management programme was added to the routine hospital care provided to the experimental group while the control group was given routine institutional care. The Brief Fatigue Inventory was used to assess fatigue, the Rhodes Index of Nausea, Vomiting and Retching was used to assess nausea and the EORTC QLQ-C30 was used to assess quality of life. Within and between group comparison of baseline and post-intervention assessments. Descriptive statistics and paired comparisons, independent-group comparisons, analysis of covariance, correlation analysis and multiple regression analysis and association test were used and p < 0.05 was considered statistically significant. Results: There were 100 cases in each experimental and control groups. Experimental group mean age was 53.07 ± 10.23 years and control group was 51.59 ± 9.51 years. This was a primary outcome analysis of this study, which showed greater improvement in the experimental group in all three outcomes. Fatigue was reported at 4.44 ± 1.70 at post test with a mean change of 1.61 points and a pre test to post test change of 6.05 ± 1.50, with this study statistical output also reporting a decrease in fatigue at post test. Nausea decreased from 15.80 ± 3.68 to 10.63 ± 3.87, with a reported mean change of 5.18 points. There was a reported improvement in the quality of life from 57.39 ± 12.89 to 67.15 ± 13.41, which translates to an increase in the global average score by 9.77 points. The between-group comparisons of each of these scores were statistically significant, with p < 0.001 for fatigue, nausea and global quality of life. Results from the ANCOVA also showed statistically significant adjusted group effects for fatigue (F = 282.035, p < 0.001), nausea (F = 385.094, p < 0.001) and global quality of life (F = 230.072, p < 0.001). Conclusion: The results of the present study show that the nurse-led symptom management programme resulted in significant reductions of chemotherapy-related fatigue, nausea and overall quality of life when compared with routine care. Findings are congruent with the incorporation of symptom assessment, education, and self-management support into supportive oncology nursing care and practice.