Background: The efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) as a later-line treatment for metastatic colorectal cancer (mCRC) has been demonstrated in clinical trials. Therefore, we conducted a randomized phase 2/3 study to determine whether FTD/TPI plus BEV is non-inferior to either FOLFIRI or S-1 and irinotecan plus BEV in terms of overall survival (OS) as second-line treatment in patients with mCRC. Methods: Patients with histologically confirmed mCRC who failed first-line doublet chemotherapy including fluoropyrimidine plus oxaliplatin with either BEV or an anti-EGFR antibody (in cases of RAS wild-type) were eligible. Patients were randomized to receive either FTD/TPI plus BEV (experimental group, BEV 5.0 mg/kg on days 1 and 15, FTD/TPI 35 mg/m² twice daily on days 1–5 and 8–12 of each 28-day cycle) or either FOLFIRI or S-1 and irinotecan plus BEV (control group). The primary endpoint was the OS. The non-inferiority margin of a hazard ratio (HR) of 1.33 was based on the assumption of a median survival time of 19 months for the control (power 0.80, 1-sided alpha 0.025). The secondary endpoints were the progression-free survival (PFS), response rate (RR), disease control rate (DCR), time to treatment failure, time to post-study treatment failure, proportion of patients receiving post-study treatment, quality of life, and safety. Results: As a result of the interim analysis for futility, the study was terminated in July 2020, and 397 patients were finally enrolled at 65 institutions from October 2017. The baseline characteristics were similar between the groups. The median OS were 14.8 months in the FTD/TPI plus BEV group and 18.1 months in the control group [HR: 1.38; 95% confidence interval (CI): 0.99–1.93; p = 0.5920 for non-inferiority]; non-inferiority of FTD/TPI plus BEV was not demonstrated. The median PFS were 4.5 months in the FTD/TPI plus BEV group and 6.0 months in the control group (HR: 1.45; 95% CI: 1.14–1.84). The RR and DCR were 3.8% and 61.2% in the FTD/TPI plus BEV group, respectively, and 7.1% and 71.7% in the control group, respectively. The proportions of patients receiving post-study treatment in the FTD/TPI plus BEV and control groups were 59.9% and 52.3%, respectively. The main grade 3 or 4 adverse events in the FTD/TPI plus BEV and control groups were neutropenia (65.8% and 41.6%, respectively), diarrhea (1.5% and 7.1%, respectively), and grade 1 or 2 alopecia (3.6% and 24.9%, respectively). Conclusions: FTD/TPI plus BEV did not show non-inferiority to FOLFIRI or S-1 and irinotecan plus BEV as second-line treatment in patients with mCRC. Post hoc subgroup analyses are ongoing to investigate patients who likely benefit from FTD/TPI plus BEV. Clinical trial information: jRCTs031180122.