OBJECTIVES: Economic evaluations of interventions for people with mental-physical multimorbidity, including a depressive disorder, are sparse. This study examines whether such interventions in adults are cost-effective. DESIGN: A systematic review. DATA SOURCES: MEDLINE, CINAHL Plus, PsycINFO, Cochrane CENTRAL, Scopus, Web of Science and NHS EED databases were searched until 5 March 2022. ELIGIBILITY CRITERIA: We included studies involving people aged ≥18 with two or more chronic conditions (one being a depressive disorder). Economic evaluation studies that compared costs and outcomes of interventions were included, and those that assessed only costs or effects were excluded. DATA EXTRACTION AND SYNTHESIS: Two authors independently assessed risk of bias in included studies using recommended checklists. A narrative analysis of the characteristics and results by type of intervention and levels of healthcare provision was conducted. RESULTS: A total of 19 studies, all undertaken in high-income countries, met inclusion criteria. Four intervention types were reported: collaborative care, self-management, telephone-based and antidepressant treatment. Most (14 of 19) interventions were implemented at the organisational level and were potentially cost-effective, particularly, the collaborative care for people with depressive disorder and diabetes, comorbid major depression and cancer and depression and multiple long-term conditions. Cost-effectiveness ranged from £206 per quality-adjusted life year (QALY) for collaborative care programmes for older adults with diabetes and depression at primary care clinics (USA) to £79 723 per QALY for combining collaborative care with improved opportunistic screening for adults with depressive disorder and diabetes (England). Conclusions on cost-effectiveness were constrained by methodological aspects of the included studies: choice of perspectives, time horizon and costing methods. CONCLUSIONS: Economic evaluations of interventions to manage multimorbidity with a depressive disorder are non-existent in low-income and middle-income countries. The design and reporting of future economic evaluations must improve to provide robust conclusions. PROSPERO REGISTRATION NUMBER: CRD42022302036.