Background: Metastatic colorectal cancer (mCRC) imposes a heavy tumor burden worldwide due to limited availability of therapeutic drugs. Aflibercept, a kind of recombinant protein of the anti-vascular endothelial growth factor (VEGF) family, has been approved in clinical application among mCRC patients since 2012. A comprehensive analysis of the efficacy, safety, and cost-effectiveness of aflibercept in mCRC treatment is necessary. Objective: To evaluate the efficacy, safety, and cost-effectiveness of aflibercept for the treatment of mCRC in order to provide a decision-making reference for the selection of targeted drugs for second-line treatment of mCRC in Hong Kong, Macao, and Taiwan regions of China and the selection of new drugs for medical institutions in these regions. Methods: A systematic retrieve on databases including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu, as well as relevant websites and databases of health technology assessment including the National Institute of Health and Clinical Optimization, Centre for Evaluation and Communication at the University of York, and the Canadian Agency for Medicines and Health Technology, was conducted. The literature was screened according to the inclusion and exclusion criteria, and data were extracted and analyzed by two authors, while the quality of the literature was assessed. Results: Finally, we included two HTA reports, 11 systematic reviews/meta-analyses, and two cost-effectiveness studies in the rapid health technology assessment. For mCRC patients receiving second-line treatment, aflibercept combined with FOLFIRI significantly increased progression-free survival (PFS) and overall survival (OS) and the objective response rate (ORR) also improved, compared with folinic acid + fluorouracil + irinotecan (FOLFIRI). In terms of safety, mCRC patients who received aflibercept combined with FOLFIRI therapy had a higher incidence of grade 3–4 adverse events than those who received FOLFIRI alone, including anti-VEGF–related adverse events (hypertension, hemorrhagic events, and proteinuria) and chemotherapy-related adverse events (diarrhea, weakness, stomatitis, hand-foot syndrome, neutropenia, and thrombocytopenia). In terms of cost-effectiveness, two economic studies conducted in the United Kingdom and Japan, respectively, found that compared with FOLFIRI, aflibercept combined with FOLFIRI had no cost-effectiveness advantage in mCRC patients receiving second-line treatment. Conclusion: Compared with FOLFIRI treatment, aflibercept combined with FOLFIRI for the second-line treatment of mCRC patients has better efficacy, worse safety, and is not cost-effective. More high-quality clinical studies are required for further exploration of aflibercept’s clinical value. Medical institutions in Hong Kong, Macao, and Taiwan regions of China should be cautious when using or introducing aflibercept plus FOLFIRI as a mCRC treatment.