OBJECTIVE: This study systematically reviewed the effect of melatonin (MLT) on quality of life (QoL) and symptoms among patients with cancer. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Cochrane Library, PubMed, Embase, Web of Science, Medline, CINAHL, Scopus, ClinicalTrials.gov, China Biology Medicine (CBM), ProQuest and Open Grey were searched from inception to November 2021. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) assessing the effects of MLT on QoL, sleep quality, fatigue, depression, pain, stomatitis rate and stomatitis severity in adult patients with cancer, without language restrictions. Studies that reported the effects of MLT along with other interventions and had incomplete or absent outcome data were excluded. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data, and another two reviewers assessed the risk of bias. The risk of bias for each eligible study was assessed using the Cochrane assessment tool. The mean difference or standard mean difference (SMD) with 95% CIs was used in the computation of continuous variables to synthesise data. The relative risk was used for dichotomous outcomes. Heterogeneity was assessed and quantified (I RESULTS: A total of 19 qualified studies that included 2101 patients with cancer (MLT: 1078, control: 1023) were included in the meta-analysis. The results indicated that MLT had no significant effect on QoL (SMD=-0.01, 95% CI (-0.14 to 0.11), p=0.83), sleep quality (SMD=-0.18, 95% CI (-0.62 to 0.26), p=0.42), fatigue (SMD=-0.34, 95% CI (-0.73 to 0.06), p=0.10), pain (SMD=-0.34, 95% CI (-0.7 to 0.02), p=0.06) or stomatitis severity (RR=0.78, 95% CI (0.47 to 1.30), p=0.35). MLT reduced stomatitis rate among patients with cancer (RR=0.47, 95% CI (0.26 to 0.88), p=0.02), except those with head and neck cancer (RR=1.09, 95% CI (0.92 to 1.29), p=0.35). MLT eased depression in patients who received administration for more than 14 days (SMD=-0.14, 95% CI (-0.27 to -0.01), p=0.03) and those who underwent surgery (SMD=-0.17, 95% CI (-0.32 to -0.03), p=0.02). CONCLUSION: The findings showed that MLT did not improve the QoL, sleep quality, fatigue, pain or stomatitis severity among patients with cancer. It had a limited effect on decreasing the stomatitis rate and easing depression. Different treatments, durations and cancer types were the main sources of heterogeneity. Further large-scale RCTs are urgently needed. In addition, the effects of different combinations of MLT dosage and duration, administration types and joint measures are worthy of further study. PROSPERO REGISTRATION NUMBER: CRD42021292855.