Given the role of chondroitin polymerizing factor (CHPF) in several cancers, we investigated its role in the progression of colorectal cancer (CRC) and its association with NLRP3 inflammasome activation. High expression of CHPF in CRC predicted poor patient prognosis. Using colony formation, EdU staining, wound healing, Transwell invasion, and flow cytometry assays, we revealed that the downregulation of CHPF inhibited the malignant behavior of CRC cells. CHPF promoted NLRP3 inflammasome activation by inducing the MAPK signaling pathway, as evidenced by enhanced expression of Phos-ERK1/2, Phos-MEK1, Phos-MEK2, and NLRP3. Additionally, nuclear factor 1 C-type (NFIC) was revealed as a potential upstream transcription factor of CHPF in the modulation of CRC, and the anti-tumor effects elicited through its knockdown were compromised by CHPF in vitro and in vivo. In summary, we demonstrated that NFIC promoted NLRP3 activation to support CRC development via the CHPF-mediated MAPK signaling.