Background: As standard third-line treatments for metastatic colorectal cancer, regorafenib and fruquintinib, compared with placebo, increase median overall survival by 2.5 months and 2.7 months, respectively. Given the incremental clinical benefit, we aim to estimate the cost effectiveness of regorafenib versus fruquintinib in the third-line treatment for patients with metastatic colorectal cancer from Chinese payer perspective. Methods: A mathematical Markov model was established to project the cost-effectiveness of regorafenib versus fruquintinib from the CONCUR and FRESCO clinical trials. Quality-adjusted-life-years (QALYs) were analyzed with extracted data from the trials. Willingness to pay (WTP) of $26508 was used. Drug costs were estimated from the perspectives of the health care system in the People’s Republic of China. One way sensitivity and scenario analyses were performed by varying potentially modifiable parameters of the model. Results: Fruquintinib, compared with regorafenib, provided an additional 0.028 QALYs (0.274 QALYs versus 0.246 QALYs) at less cost ($33536 versus $35607). Conclusions: Fruquintinib is more cost-effective than regorafenib as the third-line management for patients with metastatic colorectal cancer when WTP is $26508.