Background: Trifluridine/tipiracil (FTD/TPI) and regorafenib (REG) are standard of care for refractory metastatic colorectal cancer (mCRC). Several phase II trials of FTD/TPI plus bevacizumab (BEV) have been conducted, showing promising efficacy with manageable safety, and it is widely used for patients with refractory mCRC in Japan. No result has been reported for large-scale real-world data directly comparing FTD/TPI plus BEV with FTD/TPI or REG monotherapy. Here, we evaluated the efficacy and safety of FTD/TPI plus BEV in real-world clinical practice. Methods: We used a nationwide claims database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan) in Japan. Eligible patients were aged 20 years or older in mCRC who received their first dose of FTD/TPI or REG between May 2014 and January 2021. The primary outcome was overall survival (OS) in a propensity score matching (PSM) population that was performed matching using a 1:1 ratio for FTD/TPI plus BEV and control group (FTD/TPI or REG) by propensity score. To enhance robustness, sensitivity analyses of OS were performed using the inverse probability treatment weighted (IPTW) approach and the analysis in all eligible population. Main secondary outcomes were OS for subgroups, time to treatment discontinuation (TTD), adverse events (assessed in all eligible population), and post-treatment. Results: The eligible population was 2,369 for FTD/TPI plus BEV and 9,318 for control group (FTD/TPI: 6,500 and REG: 2,818). The PSM population was 1,787 for FTD/TPI plus BEV and 1,787 for control group (FTD/TPI: 1,252 and REG: 535). Median OS (mOS) was 17.0 months for FTD/TPI plus BEV and 11.6 months for control group (HR: 0.70; 95% CI: 0.63–0.78; P < 0.001) in PSM population. Similarly, mOS was longer for FTD/TPI plus BEV compared to that for control group in IPTW analyses (HR: 0.68; 95% CI: 0.65–0.71; P < 0.001) and in all eligible population (HR: 0.68; 95% CI: 0.63–0.73; P < 0.001). In all eligible population, mOS were 17.6 months for FTD/TPI plus BEV and 12.6 months for control group (FTD/TPI: 12.9 months and REG: 12.1 months). Median TTD was 101 days for FTD/TPI plus BEV and 56 days for control group in PSM population (Wilcoxon rank-sum test P < 0.001). The incidence of hand-foot syndrome was significantly higher in REG compared with that in FTD/TPI plus BEV (Fisher's Exact test P < 0.001. Leukopenia incidence was significantly higher in FTD/TPI plus BEV than that in REG (Fisher's Exact test P < 0.001. Granulocyte colony-stimulating factor was administered to 20.6%, 16.5%, and 1.1% of patients in FTD/TPI plus BEV, FTD/TPI, and REG, respectively. Conclusions: The real-world data showed that FTD/TPI plus BEV had significantly longer OS and TTD than FTD/TPI or REG in mCRC. Thus, FTD/TPI plus BEV may be a favorable regimen for refractory mCRC in clinical practice.