This study aimed to conduct a systematic review of the literature to identify key randomized controlled clinical trials (RCTs), followed by network meta-analysis, to compare the efficacy and safety profiles of regorafenib, fruquintinib, and TAS-102 in previously treated patients with metastatic colorectal carcinoma (mCRC). The findings showed that fruquintinib was associated with significant superiority for progression-free survival (PFS) and disease control rate (DCR) compared with TAS-102. There was no significant difference in the indirect comparison of overall survival (OS) or objective response rate (ORR) between of regorafenib, fruquintinib, and TAS-102. However, the incidence of serious adverse events (SAEs) was greater in patients treated with fruquintinib compared with regorafenib or TAS-102. These findings have relevance for clinical practice.