Oral nutritional supplements are widely recommended to head-and-neck cancer patients undergoing anti-cancer treatment; however, their effects on the outcomes of most importance to patients are unclear. This study aimed to systematically review the evidence of effect of oral nutritional supplements on mortality, treatment tolerance, quality of life, functional status, body weight and adverse effects. We searched PubMed, Embase, CENTRAL, LILACS, Web of Science, CINAHL, two trial registry platforms, three sources of grey literature and reference lists of included studies. We assessed the risk of bias using the revised Cochrane risk-of-bias tool (RoB 2), and certainty of evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. We used random-effects models with Hartung–Knapp correction for the meta-analyses. We included fifteen trials, of which five were ongoing or unpublished, providing evidence in four comparisons. We found very low to low certainty evidence for the effect of oral nutritional supplements on mortality, treatment tolerance, quality of life, functional status and adverse effects. When compared with nutritional counselling alone, nutritional counselling plus oral nutritional supplements probably increased body weight slightly. We also found adverse events relating to supplements use such as nausea, vomiting and feeling of fullness. Possible increases in mortality, treatment tolerance and quality of life besides a possible decrease in functional status are worthy of further investigation. Future research could attempt to address the clinical importance of a probable increase in body weight. Possible adverse effects of the use of oral nutritional supplements should not be overlooked.