Background: Emerging blood-based multi-cancer early detection (MCED) tests can revolutionize early cancer detection. We evaluated the potential impact of MCED screening in reducing risk of late-stage diagnosis of 12 specific cancers which represent 70% of all cancer incidence in the US. Methods: We developed Simulation Model for MCED (SiMCED), a microsimulation model of 12 solid tumor cancer types: breast, colorectal, endometrial, esophageal, gastric, kidney, liver, lung, ovarian, pancreatic, prostate, and urinary bladder. Transitions between cancer stages (I-IV) were driven by cancer type- and stage-specific dwell times, which were synthesized from published literature and empirical estimates. MCED test sensitivity was derived from the PRE-ASCEND study on average-risk American adults. The model was calibrated to reproduce yearly observed cancer incidence diagnosed symptomatically or through screening as captured in the Surveillance, Epidemiology, and End Results (SEER) database, while accounting for unobserved cancer incidence by age, sex, and cancer type and stage. Using a 50-year time horizon, we simulated 100,000 individuals aged 50 to 84 years. Diagnosis of cancer could arise from usual care (UC) or annual MCED screening. Results: Over the 50-year horizon, MCED screening of 100,000 individuals resulted in 1,323 fewer Stage IV (24%) diagnoses relative to UC, with 38% of Stage IV reductions attributed to non-screening-detectable cancer types (i.e., those without recommended screening guidelines). The table displays absolute and percentage reductions in Stage IV diagnoses for the 8 cancer types with the highest absolute reduction in Stage IV diagnoses. The percentage of Stage IV reduction was 21% for screening-detectable cancers and 29% for non-screening-detectable cancers. Conclusions: Our study suggests that MCED screening could be effective for reducing the incidence of Stage IV cancer, which is associated with the worst survival and quality of life. Of note, MCED has the potential to reduce Stage IV cancer incidence for cancers without recommended screening guidelines. However, the real-world impact of MCED tests and their cost-effectiveness require further investigation.