Background: Long-term trial evidence on the benefits of colorectal cancer (CRC) screening, particularly for novel or hybrid strategies, remains limited due to extended follow-up requirements, high costs, and ethical constraints. Simulation models have been developed to address questions unfeasible for trials.
Objectives: To  systematically synthesize model-based evidence on the long-term impact of diverse CRC screening strategies.
Methods: We systematically searched PubMed, Embase, and Web of Science for studies published between January 1, 2014, and March 3, 2025. Eligible studies were modelling studies evaluating CRC screening strategies in average-risk populations, with primary outcomes including CRC incidence, CRC-specific mortality, and all-cause mortality. Pooled risk ratios (RRs) were estimated using random-effects models, with subgroup analyses by model structure, natural history assumptions, and country. Secondary outcomes comprised a qualitative synthesis of cost-effectiveness evidence, based on incremental cost-effectiveness ratios (ICERs) relative to the willingness-to-pay (WTP) thresholds specified in the original studies.
Results: We included 102 eligible studies, assessing seven common strategies, ten emerging test-based strategies, and four hybrid strategies. All common strategies significantly reduced CRC burden compared to no screening, with 10-yearly colonoscopy achieving the greatest reductions (RR, 0.23; 95% CI, 0.19–0.28 for incidence; RR, 0.17; 95% CI, 0.14–0.21 for mortality) under perfect adherence. Emerging strategies, such as artificial intelligence (AI)-assisted colonoscopy (RR: 0.18 for CRC incidence; RR: 0.13 for CRC-specific mortality) showed great potential in reducing CRC burden. Four hybrid screening strategies also demonstrated high efficacy. Adherence significantly influenced outcomes and specific model contributed to heterogeneity. Most common screening strategies were reported as cost-effective compared to no screening within the local WTP thresholds, while certain novel screening strategies were not cost-effective at current prices.
Conclusions: Guideline-recommended strategies significantly reduce CRC burden. Novel and hybrid strategies offer promising alternatives. Real-world participation and model choice critically influence outcomes, underscoring the need to account for these factors in policy and practice.

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