Oral nutritional supplements are widely recommended to head and neck cancer patients undergoing anticancer treatment, however, their effect on outcomes of most importance to patients is unclear. This study aimed to systematically review the evidence of the 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 trials registry platforms, three sources of grey literature, and reference lists of included studies. We assessed risk of bias using the revised Cochrane risk of bias tool (RoB 2) and certainty of evidence using the GRADE approach. We used random-effects models with Hartung-Knapp correction for the meta-analyses. We included 15 trials, of which 5 were ongoing or unpublished, providing evidence in four comparisons.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 to nutritional counselling alone, nutritional counselling plus oral nutritional supplements probably increases body weight slightly. We also found adverse events related to the supplements such as nausea and vomiting, and feeling of fullness. Possible increases in mortality, in treatment tolerance, and in quality of life, besides a possible decrease in functional status, are worth of further investigation. Future research could attempt to address the clinical importance of the probable increase in body weight. Possible adverse effects of the use of oral nutritional supplements should not be overlooked.