Background & aims: Omega-3 polyunsaturated fatty acid (PUFA) supplementation has been proposed as a potential therapy for cancer-related malnutrition, which affects up to 70% of patients with cancer. The aim of this systematic review and meta-analysis was to examine the effects of oral omega-3 PUFA supplementation on muscle maintenance, quality of life, body weight and treatment-related toxicities in patients with cancer. Methods: Randomised controlled trials in patients with cancer aged ≥18 years were retrieved from 5 electronic databases: MEDLINE (via PubMed), EMBASE, CENTRAL, CINAHL (via EBSCOhost), and Web of Science, from database inception until 31st of December 2019. The quality of included studies was assessed using the Cochrane risk of bias tool. Trials supplementing ≥600 mg/d omega-3 PUFA (oral capsules, pure fish oil or oral nutritional supplements) compared with a control intervention for ≥3 weeks were included. Meta-analyses were performed in RevMan to determine the mean differences (MD) in muscle mass, quality of life and body weight, and odds ratio (OR) for the incidence of treatment-related toxicities between omega-3 PUFA and control groups with 95% confidence intervals (CI) and I 2 for heterogeneity. Results: We included 31 publications in patients with various types of cancers and degrees of malnutrition. The Cochrane risk of bias tool graded most trials as ‘unclear’ or ‘high’ risk of bias. Meta-analyses showed no significant difference between omega-3 PUFA supplements and control intervention on muscle mass, quality of life and body weight. Oral omega-3 PUFA supplements reduced the likelihood of developing chemotherapy-induced peripheral neuropathy (OR: 0.20; 95% CI: 0.10–0.40; p < 0.001; I 2 = 0%). Conclusion: This systematic review and meta-analysis indicates that oral omega-3 PUFA supplementation does not improve muscle maintenance, quality of life or body weight in patients with cancer, but may reduce the incidence of chemotherapy-induced peripheral neuropathy. Well-designed large-scale randomised controlled trials in homogenous patient cohorts are required to confirm these findings.