ABSTRACT There is considerable heterogeneity across the findings of systematic reviews of oral nutritional supplement (ONS) interventions, presenting difficulties for healthcare decision-makers and patients alike. It is not known whether heterogeneity arises from differences in patient populations or relates to methodological rigor. This overview aimed to collate and compare findings from systematic reviews of ONSs compared with routine care in adult patients who were malnourished or at risk of malnutrition with any clinical condition and to examine their methodological quality. Three electronic databases were searched to July 2019, supplemented with hand-searching. Data on all outcomes were extracted and review methodological quality assessed using A MeaSurement Tool for Assessment of systematic Reviews (AMSTAR). Twenty-two reviews were included, 11 in groups from mixed clinical backgrounds and 11 in specific clinical conditions. Ninety-one meta-analyses were identified for 12 different outcomes but there was discordance between results. Significant benefits of ONSs were reported in 4 of 4 analyses of energy intake, 7 of 11 analyses of body weight, 7 of 22 analyses of mortality, 10 of 17 analyses of complications (total and infectious), 1 of 3 analyses of muscle strength, 4 of 9 analyses of body composition/nutritional status, 2 of 14 analyses of length of stay, and 2 of 5 analyses of hospital readmissions. Ten reviews were high quality (AMSTAR scores 8–11), 9 moderate (AMSTAR scores 3–8), and 3 poor (AMSTAR scores 0–3). Methodological deficiencies were limitations to searches, poor reporting of heterogeneity, and failure to incorporate quality of evidence into any recommendations. Discordance between reviews was not markedly reduced when only high-quality reviews were considered. Evidence for the effects of ONS in malnourished patients or those who are at risk of malnutrition is uncertain, and discordance in results can arise from differences in clinical background of patients or the etiological basis of malnutrition.