Objective: The aim of this systematic review was to provide a comprehensive and detailed review of structural and methodological assumptions in model-based cost-effectiveness analyses of systemic metastatic colorectal cancer (mCRC) treatments, and discuss their potential impact on health economic outcome estimates. Methods: Five databases (EMBASE, MEDLINE, Cochrane Library, Health Technology Assessment and National Health Service Health Economic Evaluation Database) were searched on 26 August 2019 for model-based full health economic evaluations of systemic mCRC treatment using a combination of free-text terms and subject headings. Full-text publications in English were eligible for inclusion if they were published in or after the year 2000. The Consolidated Health Economic Evaluation Reporting Standards checklist was used to assess the reporting quality of included publications. Study selection, appraisal and data extraction were performed by two reviewers independently. Results: The search yielded 1418 publications, of which 54 were included, representing 51 unique studies. Most studies focused on first-line treatment (n = 29, 57%), followed by third-line treatment (n = 13, 25%). Model structures were health-state driven (n = 27, 53%), treatment driven (n = 19, 37%), or a combination (n = 5, 10%). Cohort-level state-transition modelling (STM) was the most common technique (n = 33, 65%), followed by patient-level STM and partitioned survival analysis (both n = 6, 12%). Only 15 studies (29%) reported some sort of model validation. Health economic outcomes for specific strategies differed substantially between studies. For example, survival following first-line treatment with fluorouracil, leucovorin and oxaliplatin ranged from 1.21 to 7.33 years, with treatment costs ranging from US$8125 to US$126,606. Conclusions: Model-based cost-effectiveness analyses of systemic mCRC treatments have adopted varied modelling methods and structures, resulting in substantially different outcomes. As models generally focus on first-line treatment without consideration of downstream treatments, there is a profound source of structural uncertainty implying that the cost-effectiveness of treatments across the mCRC pathway remains uncertain.