Background: The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer (mCRC) as first-line systemic treatment. However, those who progressed on standard therapies still faced the lack of optimal treatments in the third or later lines. There is a lack of data on applying triplet chemotherapy plus bevacizumab in later-line settings. We conducted a retrospective study to evaluate the efficacy and safety of modified FOLFOXIRI (mFOLFOXIRI) plus bevacizumab as a salvage regimen for patients with refractory metastatic colorectal cancer. Methods: Patients with refractory mCRC were retrospectively analyzed, who received mFOLFOXIRI plus bevacizumab in the third or later lines. The key inclusion criteria were:(1) 15-75 years old; (2) histologically confirmed mCRC; (3) treatment failure to at least two lines of treatments containing oxaliplatin, irinotecan, and 5-FU. Those with poor general condition (ECOG score > 2), or continuous grade 3-4 neuropathy and allergy to oxaliplatin were excluded. The mFOLFOXIRI regimen consists of oxaliplatin 85 mg/m² intravenous infusion for 2 hours; irinotecan 150 mg/m² intravenous infusion for 90 min; following intravenous infusion of leucovorin 400 mg/m² for 2 hours then 5-FU 2400 mg/m² for 46–48 hours continuous intravenous infusion, Q2W. Bevacizumab 5 mg/kg was administered by intravenous infusion Q2W. Results: 95 patients treated between January 2020 and December 2022 were retrospectively studied. The median age at diagnosis was 50.8 years (range 23-72 years). 50.5% of the patients had previously received at least four regimens. At the last follow-up date on December 31, 2023, the objective response rate (ORR) was 11.6% (1 complete response and 10 partial responses) and the disease control rate (DCR) was 68.4% (54 stable diseases). The median progression-free survival (PFS) was 6.2 months (95% CI, 5.4-7.0) and the median OS was 13.6 months (95% CI, 12.2-14.9). The most common adverse event was neutropenia (23.2%). Grade 3-4 adverse events were reported in 37 (38.9%) patients, including neutropenia (9.5%), oxaliplatin-related allergy (7.4%), thrombocytopenia (4.2%), thrombocytopenia (4.2%), diarrhea (4.2%), anemia (3.2%), nausea (3.2%), and neuropathy (2.1%). Conclusions: Modified FOLFOXIRI plus bevacizumab is effective as a salvage regimen in patients with refractory mCRC and with an acceptable safety profile.