Background In primary and secondary care medically unexplained symptoms (MUS) or functional somatic syndromes (FSS) constitute a major burden for patients and society with high healthcare costs and societal costs. Objectives were to provide an overview of the evidence regarding the cost-effectiveness of interventions for MUS or FSS, and to assess the quality of these studies. Methods We searched the databases PubMed, PsycINFO, the National Health Service Economic Evaluation Database (NHS-EED) and the CEA registry to conduct a systematic review. Articles with full economic evaluations on interventions focusing on adult patients with undifferentiated MUS or fibromyalgia (FM), irritable bowel syndrome (IBS) and chronic fatigue syndrome (CFS), with no restrictions on comparators, published until 15 June 2018, were included. We excluded preventive interventions. Two reviewers independently extracted study characteristics and cost-effectiveness data and used the Consensus on Health Economic Criteria Checklist to appraise the methodological quality. Results A total of 39 studies out of 1,613 articles met the inclusion criteria. Twenty-two studies reported costs per quality-adjusted life year (QALY) gained and cost-utility analyses (CUAs). In 13 CUAs the intervention conditions dominated the control conditions or had an incremental cost-effectiveness ratio below the willingness-to-pay threshold of € 50,000 per QALY, meaning that the interventions were (on average) cost-effective in comparison with the control condition. Group interventions focusing on MUS (n = 3) or FM (n = 4) might be more cost-effective than individual interventions. The included studies were heterogeneous with regard to the included patients, interventions, study design, and outcomes. Conclusion This review provides an overview of 39 included studies of interventions for patients with MUS and FSS and the methodological quality of these studies. Considering the limited comparability due to the heterogeneity of the studies, group interventions might be more cost-effective than individual interventions. Registration Study methods were documented in an international prospective register of systematic reviews (PROSPERO) protocol, registration number: CRD42017060424.