Background Malnutrition worsens the health of frail older adults. Current treatments for malnutrition may include prescribed oral nutritional supplements, which are multinutrient products containing macronutrients and micronutrients. Objective To assess the effectiveness and cost-effectiveness of oral nutritional supplements (with or without other dietary interventions) in frail older people who are malnourished or at risk of malnutrition. Data sources MEDLINE, EMBASE, Cochrane Library, Scopus, CINAHL (Cumulative Index to Nursing and Allied Health Literature) and grey literature were searched from inception to 13 September 2021. Review methods A systematic review and meta-analysis was conducted to evaluate the effectiveness and cost-effectiveness of oral nutritional supplements in frail older people (aged ≥ 65 years) who are malnourished or at risk of malnutrition (defined as undernutrition as per National Institute for Health and Care Excellence guidelines). Meta-analysis and network meta-analysis were undertaken, where feasible, along with a narrative synthesis. A cost-effectiveness review was reported narratively. A de novo model was developed using effectiveness evidence identified in the systematic review to estimate the cost-effectiveness of oral nutritional supplements. Results Eleven studies (n = 822 participants) were included in the effectiveness review, six of which were fully or partly funded by industry. Meta-analyses suggested positive effects of oral nutritional supplements compared with standard care for energy intake (kcal) (standardised mean difference 1.02, 95% confidence interval 0.15 to 1.88; very low quality evidence) and poor mobility (mean difference 0.03, p < 0.00001, 95% confidence interval 0.02 to 0.04; very low quality evidence) but no evidence of an effect for body weight (mean difference 1.31, 95% confidence interval –0.05 to 2.66; very low quality evidence) and body mass index (mean difference 0.54, 95% confidence interval –0.03 to 1.11; very low quality evidence). Pooled results for other outcomes were statistically non-significant. There was mixed narrative evidence regarding the effect of oral nutritional supplements on quality of life. Network meta-analysis could be conducted only for body weight and grip strength; there was evidence of an effect for oral nutritional supplements compared with standard care for body weight only. Study quality was mixed; the randomisation method was typically poorly reported. One economic evaluation, in a care home setting, was included. This was a well-conducted study showing that oral nutritional supplements could be cost-effective. Cost-effectiveness analysis suggested that oral nutritional supplements may only be cost-effective for people with lower body mass index (< 21 kg/m²) using cheaper oral nutritional supplements products that require minimal staff time to administer. Limitations The review scope was narrow in focus as few primary studies used frailty measures (or our proxy criteria). This resulted in only 11 included studies. The small evidence base and varied quality of evidence meant that it was not possible to determine accurate estimates of the effectiveness or cost-effectiveness of oral nutritional supplements. Furthermore, only English-language publications were considered. Conclusions Overall, the review found little evidence of oral nutritional supplements having significant effects on reducing malnutrition or its adverse outcomes in frail older adults. Future work Future research should focus on independent, high-quality, adequately powered studies to investigate oral nutritional supplements alongside other nutritional interventions, with longer-term follow-up and detailed analysis of determinants, intervention components and cost-effectiveness. Study registration This study is registered as PROSPERO CRD42020170906. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 51. See the NIHR Journals Library website for further project information.