Abstract: Chemotherapy is the primary treatment for advanced colorectal cancer (CRC). Studies have shown that first-line treatment of advanced CRC with the three-drug FOLFOXIRI (oxaliplatin + irinotecan + fluorouracil) regimen can significantly prolong progression-free survival (PFS) and overall survival (OS) compared to treatment with single-agent or double-agent fluorouracil-based regimens such as FOLFOX (oxaliplatin+fluorouracil) and FOLFIRI (irinotecan+fluorouracil). FOLFOXIRI has been considered standard treatment for untreated advanced CRC patients. This three-drug regimen with or without bevacizumab is associated with a higher objective response rate (ORR) and R0 resection rate and can be used as a conversion treatment for advanced CRC. For the RAS/BRAF wild-type CRC, FOLFOXIRI combined with an antiepidermal growth factor receptor (EGFR) antibody is expected to be another choice of conversion treatment because of its high ORR; however, there is insufficient evidence regarding this. Upfront FOLFOXIRI followed by the pre-planned reintroduction of the same regimen or a two-drug regimen after progression was proven to yield longer survival. However, in view of the challenges regarding the safety and tolerability of FOLFOXIRI, some problems remain with respect to clinical applications, requiring further discussion. This article analyzes and discusses the therapeutic value, clinical application, and improvement of the three-drug FOLFOXIRI regimen. It also reviews the application and development of the FOLFOXIRI regimen for advanced CRC.